(Fused) benz(thio)amides

ABSTRACT

A novel (fused) benz(thio)amide of the general formula: ##STR1## or a non-toxic salt thereof, wherein A represents a single bond or a group as defined in the specification; 
     B represents 
     (i) a substituted or unsubstituted carbocyclic ring of 4 to 8 members being unreplaced or optionally having one, two or three carbon atom(s) replaced by oxygen, nitrogen and/or sulfur atom(s); or 
     (ii) a divalent group of formula: ##STR2## T represents oxygen or sulfur; R 1  represents a group of general formula: ##STR3## or (iv) a straight or branched alkyl, alkenyl or alkynyl group of from 1 to 20 carbon atom(s); 
     R 2  represents hydrogen or a straight or branched alkyl group of from 1 to 6 carbon atom(s); 
     R &#39;  represents hydrogen, a halogen atom, a hydroxy group, a nitro group or a group --COOR 7  ; 
     R 4  represents: 
     (i) when B represents a closed ring, a group of the general formula: ##STR4##  wherein U represents an oxygen atom or a sulfur atom; or (ii) when B represents a divalent group, a group of the general formula: ##STR5## wherein R 5 , R 6 , R 7 , R 8 , n, m, p and q are as defined in the specification, and excluding certain compounds as defined in the specification, depending on whether A represents a single bond or a group. The compounds are useful for the prevention and/or treatment of diseases induced by leukotrienes, 5α-reductase, phospholipase and aldose reductase in mammals, especially human beings.

This is a continuation of application Ser. No. 07/516,892 filed Apr. 30,1990, now abandoned, which is a divisional of application Ser. No.07/332,930 filed Apr. 4, 1989 (now U.S. Pat. No. 4,939,141), which is adivisional of application Ser. No. 07/207,994 filed Jun. 17, 1938 (nowU.S. Pat. No. 4,847,275), which is a divisional of application Ser. No.06/767,538 filed Aug. 20, 1985 (now U.S. Pat. No. 4,780,469).

SUMMARY

This invention is related to novel (fused) benz(thio)amides.

More particularly, this invention is related to novel (fused) benz(thio)amides having an antagonistic activity on leukotrienes (SRS) andan inhibitory activity on 5α-Reductase; processes for the preparation ofthem; and pharmaceutical agent containing them as active ingredient.

BACKGROUND

In the study of prostaglandins (abbreviated as PG hereafter), manyimportant discoveries have been made continuously in recent years. Andso it was found a large change in the direction of the research anddevelopment of PG. In the compounds which have been newly found or newlyconfirmed their structure in PG family, it can be said that PGendoperoxides, (i.e. PGG₂ and PGH2), thromboxane A₂ (abbreviated as TXA₂hereafter), prostacyclin (i.e. PGI₂) and leukotriene C₄, D₄ and E₄(abbreviated as LTC₄, LTD₄ and LTE₄, respectively, hereafter) etc. haveespecially strong and unique biological activities.

All the compounds of PG family containing various PG previously knownwell in addition to the above compounds, are biosynthesized from thesame mother compound, i.e. arachidonic acid in a living body and,therefore, the metabolic routes starting from arachidonic acid is called"Arachidonate cascade" as a whole. The detailed explanation of eachroute and the pharmacological character of each metabolite are describedin Igaku No Ayumi, 114, 378 (1980), ibid, 114, 462 (1980), ibid, 114,866 (1980), ibid, 114, 929 (1980), Gendai Iryo, 12, 909 (1980), ibid,12, 1029 (1980), ibid, 12, 1065 (1980) and ibid, 12, 1105 (1980) etc.

The arachidonate cascade can be largely divided into two routes; one isthe route that cyclooxygenase acts on arachidonic acid to convert, intovarious PGs, e.g. prostaglandin F₂ (abbreviated PGF₂ hereafter),prostaglandin E₂ (abbreviated PGE₂ hereafter), PGI₂, TXA₂, via PGG₂ andfurther PGH₂ and the other is the route that lipoxygenase acts onarachidonic acid to convert, in hydroxyeicosatetraenoic acid(abbreviated as HETE hereafter) or leukotrienes, viahydroperoxyeicosatetraenoic acid (abbreviated HPETE hereafter).

As the former route is well known, it is not described in the presentspecification in detail. See Prostaglandin (1978), edited by MakotoKatori et al., published by Kohdan-sha.

Concerning the latter route, it has been known that various compoundsare produced according to the following scheme I. ##STR6##

Besides being metabolized through a well known route, i.e. the route viaPG endoperoxides, arachidonic acid is also metabolized through anotherroute by the action of lipoxygenase. That is to say, arachidonic acid ismetabolized by the action of lipoxygenase, e.g. 5-lipoxygenase,12-lipoxygenase and 15-lipoxygenase, to 5-HPETE, 12-HPETE and 15-HPETE,respectively.

These HPETE are converted into 5-HETE, 12-HETE and 15-HETE,respectively, by the action of peroxidase converting a hydroperoxy groupinto a hydroxy group. Furthermore, LTA₄ is also produced from 5-HPETE bydehydration. LTA₄ is converted into leukotriene B₄ (abbreviated as LTB₄hereafter) or LTC₄ enzymatically. Further, LTC₄ is converted into LTD₄by the action of γ-glutamyl transpeptidase.

Moreover, it was recently defined that LTD₄ is metabolized to LTE₄ (seeBiochem. Biophys. Res. Commun., 91, 1266 (1979) and Prostaglandins,19(5), 645 (1980)).

Besides, SRS is an abbreviation of Slow Reacting Substance and it wasnamed by Feldberg et al. for the substance released when perfusing cobravenom through isolated lung or incubating cobra venom with vitellus. Andit was reported that the substance constricted ilem isolated from guineapig slowly and continually (see J. Physiol., 94, 187 (1938)).

Moreover, Kellaway et al. showed the relation between SRS-A and allergicreaction from the fact that SRS-A is released when an antigen issensitized to perfusing lung isolated from guinea pig (see Quant. J.Exp. Physiol., 30, 121 (1940)).

Brocklehurst reported that when the antigen is sensitized to a lungfragment isolated from a bronchial asthmatics whose specific antigen isdefined, by an operation, histamine and SRS-A are released and stronglyconstrict bronchial muscle. Since such constriction can not be preventedby an antihistaminic agent, he suggested that SRS-A is an importantbronchoconstrictor in an asthmatic paroxysm (see Progr. Allergy, 6, 539(1962)).

Since then, many reports were published, for instance, SRS-A preparedfrom human lung slice constrict a tracheal spiral of normal human (seeInt. Arch. Allergy Appl. Immunol., 38, 217 (1970)); when SRS-A preparedfrom rats is injected intravenously to guinea pig, significant increaseof pulmonary resistance is observed (see J. Clin. Invest., 53, 1679(1974)); in addition, a subcutaneous injection of SRS-A to guinea pig,rat and monkey enhances vascular permeability

(see Advances in Immunology, 10, 105 (1969), J. Allergy Clin. Immunol.,621, 371 (1978), Prostaglandins, 19(5), 779 (1980) etc.).

Generally, the substance released by immunological reaction is calledSRS-A. On the other hand, the substance released by non-immunologicalreaction such as calcium ionophore is called SRS. However, the above twosubstances have many similarities to each other and, therefore, it isconsidered they would probably be the same substance.

Further, it was confirmed that SRS or SRS-A is a mixture of LTC₄ andLTD₄. So it can be understood that the pharmacological characters ofthese leukotrienes are the same as those of SRS or SRS-A (see Proc.Natl. Acad. Sci. USA, 76, 4275 (1979), Biochem. Biophys. Res. Commun.,91, 1266 (1979), Proc. Natl. Acad. Sci. USA, 77, 2014 (1980) and Nature,285, 104 (1980)).

Based on the results of these studies, various leukotrienes (thestructures of LTC₄, LTD₄ and LTE₄, and further other leukotrienes whichmay be confirmed in the future) biosynthesized from arachidonic acid viaLTA4, are considered to be important factors relating to the appearanceof allergic tracheal and bronchial diseases, allergic lung diseases,allergic shock and various allergic inflammations.

To surpress leukotrienes is useful for the prevention and/or treatmentof tracheal bronchial or lung diseases such as asthma, allergic lungdiseases, allergic shock or various allergic diseases.

On the other hand, arachidonic acid is released from phospholipids bythe action of phospholipase, and two routes were generally accepted that(1) one is the route that phospholipase A₂ is reacted on phosphatidylcholine, and (2) the other is the route that phospholipase C was reactedon phosphatidyl inositol to produce 1,2-diglyceride, anddiglyceridelipase followed by monoglyceridelipase were reacted on it torelease arachidonic acid (see Kagaku to Seibutsu (Chemistry andBiology), 21, 154 (1983)).

And it was known that arachidonic acid released is metabolized throughtwo different routes i.e. (1) metabolizing route to bioactive substancese.g. prostaglandins (PGs), thromboxane A₂ (TXA₂) by cyclooxygenase, and(2) metabolizing route to bioactive substances e.g. SRS-A (Slow ReactingSubstances of Anaphylaxis), hydroxyeicosatetraenoic acid (HETE) andleukotriene B₄ (LTB₄) by lipoxygenase (see Kagaku to Seibutsu (Chemistryand Biology), 21, 154 (1983)).

These metabolites are known as chemical mediators; for example, TXA₂ isa compound which have a potent activity of platelet aggregation andaotra contraction, SRS-A is a chemical mediator on asthma, LTB₄ is achemical mediator on various inflammations (e.g. gout), and PGs are alsochemical mediators on various inflammations which enhance a vascularpermeability and a pain, and have a vasodilative action, pyrogeneticaction and chemotactic action (see Prostaglandin (1978), edited byMakoto Katori et al, published by Kohdan-sha).

Arachidonic acid is converted and metabolized to various chemicalmediators which act important physiological part in living body. And itwas known that ill-balances of those chemical mediators induce variousdisorders.

And as antagonist of SRS, the groups of the compounds of generalformula: ##STR7## (wherein from R¹ to R⁵ and R⁷ each represent ahydrogen atom, a hydroxy group, an alkyl group of from 1 to 6 carbonatom(s), an alkoxy group of from 1 to 6 carbon atom(s), an amino group,an acyl group, an acylamino group of from 2 to 6 carbon atoms, analkenyl group of from 2 to 6 carbon atoms, a halogen atom or aphenylalkoxy group in which alkoxy have from 1 to 6 carbon atom(s); Xrepresents a hydrocarbyl group of from 1 to 10 carbon atom(s) beingoptionally substituted by hydroxy group(s); A represents an oxygen atomor is absent; Q represents an alkylene, alkenylene or alkynylene groupof from 2 to 6 carbon atoms which may be branched; D represents acarboxy group, a 5-tetrazolyl group or carbamido-5-tetrazolyl group.)were described in patent publications by Fisons Co., Ltd. (see JapanesePatent Application No. 55-1273841, European Patent Publication No. 17332or U.S. Pat. No 4281008).

And, the following compounds were described in the patent publication byKissei Pharmaceutical Co., Ltd, as anti-allergic agent, of the generalformula: ##STR8## (wherein R¹ and R² each represent a hydrogen atom oran alkyl group with 1-4 carbon atoms; R³ and R⁴ each represent ahydrogen atom or may be combined together to form an additional chemicalbond; X represents a hydroxyl group, a halogen atom, a straight orbranched chain saturated or unsaturated alkyl group with 1-4 carbonatoms, a straight or branched chain saturated or unsaturated alkoxygroup with 1-4 carbon atoms, an acyloxy group with 1-4 carbon atoms, ora cycloalkyl group with up to 6 carbon atoms; n is zero or an integer of1-3 with the proviso that when n is 2 or 3; X's may be the same ordifferent and that when two X's are commonly the alkyl or alkoxy group,both X's may be combined together to form a ring; and Y represents astraight or branched chain alkylene group or a straight or branchedchain oxyalkylene group connected to the benzene nucleus through anoxygen atom.) as well as physiologically acceptable salts thereof. (seeU.S. Pat. Nos. 4,026,896.)

And benzamides, i.e. compounds represented by the general formula (I)depicted hereafter, wherein the symbol B is opened and R⁴ is a group ofthe formula: --OCH₂ COOR, were described in prior patent applications bythe present inventors (see Japanese Patent Application (Kokai) Nos.60-97946, 60-116657, 60-142941 and 60-146855).

DISCLOSURE OF THE INVENTION

The present inventors have synthesized novel compounds of the generalformula (I) depicted hereafter, which have a structure characterized asa (thio)amido group being substituted on a fused benzene ring or benzenering and have found the compounds have potent antagonistic activity onleukotrienes (SRS), and then achieved the present invention.

And, the compounds of the present invention also inhibit phospholipase,so inhibit release of arachidonic acid from phospholipids, and thereforeare useful for prevention and/or treatment of diseases induced byarachidonate metabolites e.g. TXA₂, PGs, leukotrienes in mammalsincluding human beings, especially human beings.

Examples of the diseases to the subject are various allergic diseasesinduced by leukotrienes described above, thrombosis e.g. one induced byinjury (damage) of cerebral or coronary, endothelium or intima andinflammations e.g. arthritis, rheumatism (see Junkan Kagaku(Cardiovascular Science) 3, 484 (1983) Yakkyoku (Pharmacy) 34, 167(1983)).

It was found that the compounds of the present invention also have aninhibitory activity on 5α-reductase described below, besides theactivity of leukotriene antagonist and phospholipase inhibitor describedabove.

5α-Reductase presents in endoplasmic reticulum and nucleic acid, and itconverts testosterone which is taken into a target tissue, into active5α-dihydrotestosterone. The activated 5α-dihydrotestosterone inducescell proliferaction by binding to an intracelluar receptor. Activationof this enzyme is considered to cause some diseases such as prostatichypertrophy, resulting in pattern baldness and acne.

As a matter of course, the compounds of the present invention have noactivity peculiar like hormones, and inhibit 5α-reductase, so suppressincreasing of 5α-dihydrotestosterone, therefore suppress cellproliferaction, and therefore are useful for the prevention and/ortreatment of prostatic hypertrophy, male pattern baldness and acne inmammals including human beings especially human beings.

Furthermore, it was found that the compounds of the present inventionalso have an inhibitory activity on aldose reductases.

An aldose reductase is an enzyme which reduces an aldose (e.g. glucose,galactose) into the corresponding polyol (e.g. sorbitol, galactitol) inhuman beings or other animals. The sorbitol and galactitol produced bythe action of this enzyme are accumulated in the crystalline lenses, theperipheral nerves, the kidney, etc. of diabetics includinggalactosemiacs thus causing the above described complications e.g.retinopathy, diabetic cataract, nerve disturbances or renal disorders(see Jap. J. Opthamol., 20, 399 (1976), Int. Congr. Ser. Excepta Med.,403, 594 (1977) and Metabolism, 28, 456 (1979)).

The compounds of the present invention have inhibitory activity on analdose reductase and are therefore effective for the prevention and/ortreatment of diabetic complications described above in mammals includinghuman beings especially human beings.

That is the present invention relates to novel (fused) benz (thio)amides of the general formula: ##STR9## wherein, A represents a singlebond or a group of methylene, ethylene, trimethylene, tetramethylene,vinylene propenylene, butenylene, butadienylene or ethynylene groupoptionally being substituted by one, two or three of straight orbranched alkyl group(s) of from 1 to 10 carbon and/or phenyl group(s);

B represents

(i) a carbocyclic ring of from 4 to 8 members being unreplaced orreplaced one, two or three of optional carbon atom(s) by oxygen,nitrogen and/or sulphur atom(s) (the ring may optionally be substitutedby group(s) of oxo, thioxo and/or hydroxy group (s)). or

(ii) a divalent group of formula: ##STR10## T represents an oxygen or asulphur atom; R¹ represents a group of general formula: ##STR11## (iv) astraight or branched alkyl, alkenyl or alkynyl group of up to 20 carbonatoms(s);

(wherein R⁵ and R⁶ independently represent a hydrogen atom or a halogenatom or a straight or branched alkyl, alkenyl or alkynyl group of from 1to 20 carbon atom(s) being unreplaced or replaced one, two,three, fouror five of optional carbon atom(s) by oxygen atom(s), sulphur atom(s),halogen atom(s), nitrogen atom(s) , benzene ring(s) , thiophene ring(s), naphthalene ring(s), carbocyclic ring(s) of from 4 to 7 carbonatom(s), carbonyl group(s), carbonyloxy group(s), hydroxy group(s),carboxy group(s), azido group(s) and/or nitro group(s);

R² represents a hydrogen atom or a straight or branched alkyl group offrom 1 to 6 carbon atom(s);

R³ represents a hydrogen atom, a halogen atom, a hydroxy group, a nitrogroup, a group of general formula: --COOR⁷ (wherein R⁷ represents ahydrogen atom or a straight or branched alkyl group of from 1 to 6carbon atom(s)) or a straight or branched alkyl, alkoxy or alkylthiogroup of from 1 to 6 carbon atom(s);

R⁴ represents

(i) when B represents a closed ring, a group of general formula:##STR12## (wherein U represents an oxygen or a sulphur atom; R⁸represents a hydrogen atom or a straight or branched alkyl group of from1 to 6 carbon atom(s), n and m represent an integer of from 1 to 10,respectively, p and q represent zero or an integer of from 1 to 10,respectively) or

(ii) when B do not represent a ring, a group of general formula:##STR13## (wherein R⁸, p and q represent the same meaning as depictedhereinbefore, with the proviso that, when B represents a group offormula: ##STR14## p does not represent zero), with the proviso that,following compounds are excluded, i.e. compounds of general formula:##STR15## (wherein A' is a vinylene or ethylene group optionally beingsubstituted by straight or branched alkyl group(s) of from 1 to 4 carbonatom(s), R^(4') is the general formula:

    --(CH.sub.2).sub.n --COOR.sup.8

(wherein R⁸ and n are defined the same as hereinbefore)

and R_(1') is

(i) a group of the general formula: ##STR16## (wherein R^(5') and R^(6')are hydrogen atom(s), hydroxy group(s), halogen atom(s), straight orbranched alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy oracyloxy group(s) of from 1 to 4 carbon atom(s) or cycloalkyl group(s) offrom 3 to 6 carbon atom(s), independently or

(ii) a group of the general formula: ##STR17## (wherein R^(5') andR^(6') are the same meaning as depicted hereinbefore)) and non-toxicsalts thereof, and processes for their preparation, and pharmaceuticalagents including them or it as active ingredient.

The compounds of the present invention may be largely divided into thefollowing two groups in accordance with whether B is a closed ring ornot.

That is the present invention includes compounds of the general formula:##STR18## wherein A, B, R¹, R², R³, R⁴, T and U have the same meaning asdescribed hereinbefore.)

Both of the compounds of the general formula (IA) and (IB) are novelcompounds per se.

The compounds of the general formula (IA) are quite novel, in chemicalstructure, because they have a (thio)amido group as well as benzenering(s) and/or chromone skelton as the essential group, compared withthe compounds of Fisons of the general formula (A), describedhereinbefore in the background.

The compounds of the general formula (IB) are also novel compounds andhave been first found to have inhibitory activities on 5α-reductase, onlipoxygenase and on aldose reductase, besides antagonistic activity onleukotrienes.

In the general formula (I) , examples of the groups represented by R⁵and R⁶ are the following:

a hydrogen atom, a halogen atom

an alkyl group of from 1 to 20 carbon atom(s)

an alkenyl or alkynyl group of from 2 to 20 carbon atoms

an alkoxy or alkylthio group of from 1 to 19 carbon atom (s)

an alkenyloxy, alkenylthio, alkynyloxy or alkynylthio group of from 3 to19 carbon atoms

an alkyl group of from 1 to 19 carbon atom(s) substituted by halogenatom(s) and/or hydroxy group (s)

an alkenyl or alkynyl group of from 2 to 19 carbon atoms substituted byhalogen atom (s) and/or hydroxy group (s)

an alkoxy or alkylthio group of from 1 to 18 carbon atom (s) substitutedby halogen atom(s) and/or hydroxy group(s)

an alkenyloxy, alkenylthio, alkynylthio or alkynyloxy group of from 3 to18 carbon atoms substituted by halogen atom(s) and/or hydroxy group (s)

an alkyloxyalkyl, alkenyloxyalkyl or alkyloxyalkenyl group of from 2 to19 carbon atoms

a cycloalkyl, cycloalkyloxy or cycloalkylthio group of from 4 to 7carbon atoms

a phenyl, phenoxy or phenylthio group

an alkyl group of from 1 to 19 carbon atom(s) which has carbocyclicring(s) of from 4 to 7 carbon atoms, benzene ring(s), naphthalenering(s) or thiophene ring(s) in the middle or at the terminal thereof

an alkoxy, alkylthio, alkenyloxy, alkenylthio, alkynyloxy or alkynylthiogroup of from 1 to 18 carbon atom(s) which have carbocyclic ring(s) offrom 4 to 7 carbon atoms, benzene ring(s), naphthalene ring(s) orthiophene ring(s) in the middle or at the terminal thereof

a phenylthioalkoxy or phenyloxyalkyloxy group wherein the alkyl moietyis a group from 1 to 17 carbon atom(s)

a carboxyalkyloxy or alkoxycarbonylalkyloxy group of from 2 to 19 carbonatoms

an alkoxycarbonyloxyalkyloxy group of from 3 to 19 carbon atoms

an alkenylcarbonyloxy group of from 3 to 20 carbon atoms

an alkylcarbonyl group of from 2 to 20 carbon atoms

an azidoalkyl, nitroalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl group of from 1 to 19 carbon atom(s)

an azidoalkyloxy, nitroalkyloxy, aminoalkyloxy, alkylaminoalkyloxy,dialkylaminoalkyloxy group of up to 18 carbon atom(s)

an alkenylcarbonylamino group of from 3 to 19 carbon atoms

an alkylamino group of from 1 to 19 carbon atom(s)

groups described above further substituted by halogen atom(s), hydroxygroup(s), azido group(s), nitro group(s) and/or carboxy group(s)

Among the groups described above, preferable groups as R⁵ and R⁶ are thefollowing groups:

a hydrogen atom

a halogen atom

a straight or branched alkyl group of from 1 to 20 carbon atom(s)

a straight or branched alkoxy group of from 1 to 19 carbon atom(s)

a straight or branched alkenyloxy group of from 3 to 19 carbon atoms

a straight or branched alkynyloxy group of from 3 to 19 carbon atoms

a straight or branched alkylthio group of from 1 to 19 carbon atom(s)

a straight or branched alkyl group of from 1 to 18 carbon atom(s) beingsubstituted by halogen atom(s)

a straight or branched alkyloxyalkyl group of from 2 to 19 carbonatom(s)

a cycloalkyl, cycloalkylalkyl (wherein alkyl moiety is a group of from 1to 8 carbon atom(s)) or cycloalkylalkyloxy (wherein alkyl moiety is agroup of from 1 to 8 carbon atom(s)) group optionally substituted bystraight or branched alkyl group(s) of from 1 to 8 carbon atom(s),hydroxy group(s), halogen atom(s) and/or nitro group (s)

a phenyl, phenylalkyl (wherein alkyl moiety is a group of from 1 to 8carbon atom(s)), phenylalkyloxy (wherein alkyl moiety is a group of from1 to 8 carbon atom(s)) or phenylalkenyloxy (wherein alkenyl moiety is agroup of from 2 to 8 carbon atom(s) ) group optionally substituted bystraight or branched alkyl group(s) of from 1 to 8 carbon atom (s),hydroxy group (s), halogen atom (s) and/or nitro group (s)

a naphthyl, naphthylalkyl (wherein alkyl moiety is a group from 1 to 8carbon atom(s)), naphthylalkoxy (wherein alkyl moiety is a group from 1to 8 carbon atom(s)) or naphthylalkenyloxy (wherein alkenyl moiety is agroup from 2 to 8 carbon atoms) group optionally substituted by straightor branched alkyl group(s), hydroxy group, halogen atom(s) and/or nitrogroup(s)

a straight or branched alkoxy, alkenyloxy or alkyloxyalkyloxy group offrom 1 to 18 carbon atom(s) substituted by carbonyl, carbonyloxy and/orhydroxy group(s)

a straight or branched alkoxy group of from 1 to 17 carbon atom(s)substituted by phenoxy or phenylthio group(s)

a straight or branched alkoxy group of from 1 to 18 carbon atom(s)substituted by thiophene ring(s)

a straight or branched alkyl, alkenyl, alkoxy or alkenyloxy group offrom 1 to 18 carbon atom(s) substituted by azido or nitro group(s) oramino group(s) optionally substituted by an alkyl group of from 1 to 6carbon atom(s) (including dialkylamino group(s))

a straight or branched alkyl, alkenyl, alkoxy or alkenyloxy group offrom 1 to 18 carbon atom(s) replaced by two kinds groups which arecarbonyl group(s) and amino group(s)

An alkyl group of from 1 to 20 carbon atom(s) in the present inventionmeans a group of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl,hexadecyl, heptadecyl, octadecyl, nonadecyl, eicocyl group and anisomeric group thereof.

And an alkenyl and alkynyl group of from 1 to 20 carbon atom(s) meancorresponding groups described above.

An alkyl group of from 1 to 6 carbon atom(s) in the present inventionmeans a methyl, ethyl, propyl, butyl, pentyl, or hexyl group, or anisomeric group thereof.

A cycloalkyl group of from 4 to 7 carbon atoms in the present inventionmeans a cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group

A halogen atom in the present invention means a chlorine, bromine,iodine or fluorine atom.

In the present invention, when a certain carbon atom is replaced byanother atom, a ring or a group, any carbon atom(s) can be replaced, sofar as the replacement per se can be acceptable chemically orphysically. For example, "an isobutyl group replaced by a benzene ringin the middle or at the terminal" means an isopropylphenyl,dimethylphenylmethyl or 2-phenylpropyl group. When a carbon atom isreplaced, hydrogen atom(s) may be added or removed suitably. Forexample, "a pentyl group replaced by a nitrogen atom at the 2ndposition" means N-propylaminomethyl group.

For example, a 2-(phenoxy)ethoxy group and a5-(2-chloro-4-nitrophenylthio)-5-methylpent-2-enyloxy group are replacedby one, two, three, four or five optional carbon atoms from pentyl and6,8-dimethylnon-3-enyl groups, respectively, and are included in thepresent invention, as illustrated in the following examples, which aremerely illustrative and are not to be construed as limiting the scope ofthe present invention in any way: ##STR19##

And examples of carbocyclic rings of from 4 to 8 members beingunreplaced or replaced one, two or three of optional carbon atom byoxygen, nitrogen and/or sulphur atom(s) (the ring may optionally besubstituted by group(s) of oxo, thioxo and/or hydroxy group(s))represented by in the general formula (I) are the following: ##STR20##(The rings above described may optionally be substituted by hydroxygroup(s).)

The carbocyclic rings depicted above may be saturated rings orunsaturated ones, or aromatic rings or non-aromatic ones.

Any rings depicted above are preferable. And, when the rings are fusedwith benzene rings, the following fused benzene rings are especiallypreferable, i.e. the rings of the general formula: ##STR21## are thefollowing rings: ##STR22##

And compound wherein B is a opened group of the formula: ##STR23## arealso preferable. Process for the Preparation (1)

The present invention includes not only the compounds per se, non-toxicsalts thereof, use or method, but also process for the preparation.

According to the present invention, the compounds of the presentinvention of the general formula (I) may be prepared by reacting acompound of general formula:

    R.sup.1 --A--COOH                                          (II)

(wherein R¹ and A have the same meaning as described hereinbefore) or acorresponding dithioic acid and a compound of general formula: ##STR24##(wherein B, R², R³ and R⁴ have the same meaning as describedhereinbefore.) to form amide-bond, and further subjecting the productthereof to saponification and/or esterification, if desired.

Reactions to form amide-bond are well known, it may be carried out, forexample;

(A) by the method with using mixed acid anhydride

(B) by the method with using acid halide

(C) by the method with using DCC (Dicyclohexylcarbodiimide).

Concrete description of the methods described above are as follows:

(A) method with using mixed acid anhydride may be carried out, forexample; an acid of the general formula (II) is reacted with an acidhalide (pivaloyl chloride, thionyl chloride, tosyl chloride, mesylchloride, oxalyl chloride etc.) or an acid derivative (ethylchloroformate, isobutyl chloroformate etc.) in an inert organic solvent(chloroform, methylene chloride, diethyl ether, THF etc.) or withoutsolvents, in the presence of tertiary amine (pyridine, triethylamine,picoline etc.), at from 0° C. to 40° C. to give a mixed acid anhydride.The obtained acid mixed anhydride and an amine of the general formula(III) are reacted in an inert organic solvent (described above), at from0° C. to 40° C.

(B) method with using acid halide may be carried out, for example; anacid of the general formula (II) is reacted with an acid halide(described above ) in an inert organic solvent (described above) orwithout solvents at from -20° C. to a refluxing temperature of thesolvent used to give an acid halide. The obtained acid halide and anamine of the general formula (III) are reacted in an inert organicsolvent (described above) in the presence or absence of tertiary amine(described above) at from 0° C. to 40° C.

(C) method with using DCC may be carried out, for example; an acid ofthe general formula (II) and an amine of the general formula (III) arereacted in an inert organic solvent (described above) or withoutsolvents in the presence or absence of tertiary amine (described above)using with DCC at from 0° C. to 40° C.

Preferably, the reactions (A), (B) and (C) described above are carriedout in an atmosphere of inert gas (argon, nitrogen, etc.) underanhydrous conditions.

Process for the Preparation (2)

Among the compounds of the present invention, compounds of the generalformula: ##STR25## (wherein R²⁰ represents methylene group or a singlebond, and A, B, R¹, R², R³ and T have the same meaning as describedhereinbefore.) may be prepared by reacting a compound of the generalformula: ##STR26## (wherein A, B, R¹, R² R³, R²⁰ and T have the samemeaning as described hereinbefore) with an azide.

Reactions to induce a 2-tetrazolyl group from a cyano group with anazide are known, it may be carried out, for example, under anhydrousconditions,using with azide (sodium azide, lithium azide, potassiumazide etc.), in the presence of weak acid (pyridium chloride, ammoniumchloride, dimethylaniline hydrochloride etc.) in an inert organicsolvent (dimethylformamide, N-methylpyrrolidone etc.) with heating.

Process for the Preparation (3)

Among the compounds of the present invention, compounds of the generalformula: ##STR27## (wherein R⁵⁵ represents a hydrogen atom or a straightor branched alkyl group of from 1 to 6 carbon atom(s), and A, R¹, R³,R²⁰ and T have the same meaning as described hereinbefore) may beprepared by reacting a compound of general formula: ##STR28## (whereinR¹, R³, A and T have the same meaning as described hereinbefore) and acompound of general formula: ##STR29## (wherein X¹⁰ and X²⁰ representhalogen atoms respectively, and R⁵⁰ represents a straight or branchedalkyl group of from 1 to 6 carbon atom(s), and R²⁰ has the same meaningas described hereinbefore) and further, subjecting the product thereofto esterification and/or saponification, if desired.

Reactions to form a benzodioxane ring from catechol are known, and itmay be carried out, for example, under anhydrous conditions, in thepresence of a condensing agent (potassium carbonate, sodium carbonateetc.) in an inert organic solvent (acetone, methyl ethyl ketone, dioxaneetc.), with heating.

Process for the preparation (4)

Among the compounds of the present invention, compounds of the generalformula: ##STR30## (wherein R¹²¹ represents a group of general formula:--(CH₂)_(r) -- (wherein r represents zero or an integer of from 1 to 9);R¹⁴⁰ represents a group of general formula: --COOR⁸ (wherein R⁸ has thesame meaning as described hereinbefore) or a group of formula: ##STR31##And A, R¹, R², R³, T and U have the same meaning as describedhereinbefore.) may be prepared by reacting a compound of generalformula: (wherein A, R¹, R², R³, T and U have the same meaning asdescribed hereinbefore) and a compound of general formula:

    X.sup.110 --CH.sub.2 --R.sup.121 --R.sup.140               (XXXXVI)

(wherein X¹¹⁰ represents a halogen atom, and R¹²¹ and R¹⁴⁰ have the samemeaning as described hereinbefore) and further subjecting the productthereof to saponification and/or esterification, if desired.

Reactions of O-alkylation are known, and it may be carried out, forexample, under anhydrous conditions, in the presence of a base (sodiumhydride, potassium carbonate, sodium carbonate etc.), in a polar aproticsolvent (diethyl ether, tetrahydropyran, acetone etc.) at from 0° C. to100° C.

Process for the Preparation (5)

Among the compounds of the present invention of the general formula (I),certain compounds may be prepared from the corresponding compounds ofthe present invention.

For example, it may be carried out in the following reaction formula andreaction scheme [A]. ##STR32## (in the above case, a reaction startingwith a compound of formula (Ic) which substitutes a butadienylene andbutenylene group , or group substituted by an alkyl or phenyl group forthe vinylene group may also be carried out similarly) ##STR33## (whereinthe symbol represents whole group of the substituent R¹ and symbolstherein are included in R¹ respectively. R¹ and groups in R¹ have thesame meaning as described above in the following schemes. R³⁰ representsan alkyl, alkenyl or alkynyl group of from 1 to 18 carbon atom(s).)##STR34##

Each symbol in the scheme [A] represents the following meanings or asdefined hereinbefore respectively.

R⁴⁰, R⁴¹ --an alkyl, alkenyl or alkynyl group of from 1 to 18 carbonatom(s)

R⁴⁵ --a hydrogen atom or an alkyl, alkenyl or alkynyl group of from 1 to18 carbon atom(s)

T¹⁰ --an oxygen atom or a sulphur atom, or an imido group

M¹⁰ --a lithium, potassium or sodium atom

X¹ --a halogen atom

Processes for the Preparation of Intermediates

Intermediates described hereinbefore of the general formula (III), (IV),(V) and (XXXXV) may be prepared by the processes described in thefollowing reaction schemes, respectively.

Each symbol in the schemes represent the following meanings or asdescribed hereinbefore, respectively.

R²¹ --a straight or branched alkyl group of from 1 to 6 carbon atom(s)

R⁵¹, R⁵², R⁵³, R⁵⁶ --a straight or branched alkyl group of from 1 to 6carbon atom(s)

R⁵⁴ --a hydrogen atom or a straight or branched alkyl group of from 1 to6 carbon atom(s)

R⁷⁰,R⁷¹ --a trifluoroacetyl group

X³⁰,X⁴⁰,X⁵⁰ --a halogen atom

R¹²²,R¹⁸⁰ --a straight or branched alkyl group of from 1 to 6 carbonatom(s)

R¹²⁵ --a group of formula: --U--(CH₂)_(n) -- or --(CH₂)_(p) -- (whereinU, n and p have the same meaning as described hereinbefore)

R¹⁵⁰ --a trifluoroacetyl group

X¹²⁰,X¹³⁰,X¹⁴⁰,X¹⁵⁰ --a halogen atom

When B contains an imino group, it is preferable to protect by trifluorogroup(s) etc., and to remove the protecting group(s) in a suitable step.

And compounds of the general formula (IIIj) may be prepared by the sameprocedure as the method to obtain compounds of general formula (IIIh)from compounds of general formula (IIIg). ##STR35##

Intermediates having a 1,4-dithianaphthalene skeleton also may beprepared using with a compound of general formula: ##STR36## (wherein R³has the same meaning as described hereinbefore) which may be obtained byhydrolyzing a compound of general formula: ##STR37## (wherein R³ has thesame meaning as described hereinbefore) instead of the compound of thegeneral formula (XIII).

In the processes for the preparation of the compounds of the presentinvention, esterification and saponification may be carried out asfollows.

Conversion of a certain acid into a corresponding ester (i.e.esterification)is a known reaction per se, and it may be carried out,for example;

(1) by the method using a diazoalkane

(2) by the method using an alkyl halide

(3) by the method using DMF-alkylacetal and

(4) by the method reacting with a corresponding alkanol

Concrete descriptions of the reactions above-mentioned are as follows:

(1) the method using a diazoalkane may be carried out, for example, inan inert organic solvent (diethyl ether, ethyl acetate, methylenechloride, acetone, methanol, ethanol etc.) using with correspondingdiazoalkane.

(2) the method using an alkyl halide may be carried out, for example, inan organic solvent (acetone, N,N-dimethylformamide, DMSO etc.), in thepresence of a base (potassium carbonate, sodium carbonate, sodiumbicarbonate, potassium bicarbonate, calcium oxide etc.) using with acorresponding alkyl halide.

(3) the method using DMF-dialkylacetal may be carried out, for example,in an inert organic solvent (benzene, toluene etc.) using with acorresponding DMF-dialkylacetal.

(4) the method reacting with a corresponding alkanol may be carried out,for example, in a corresponding alkanol, using an acid (hydrochloricacid, sulphuric acid, p-toluenesulphonic acid, hydrochloride gas etc.)or condensing agent (DCC, pivaloyl chloride, arylsulphonyl halide,alkylsulphonyl halide etc.).

Reactions mentioned above are carried out generally at from -10° C. to100° C.; and they may be carried out with a further addition of inertorganic solvent (s) (THF, methylene chloride etc.) not related to thereactions.

Conversion of a certain ester into corresponding acid (i.e.saponification)is a known reaction per se, and it may be carried out,for example;

(1) using with an aqueous solution of an alkali (potassium hydroxide,sodium hydroxide, lithium hydroxide, potassium carbonate, sodiumcarbonate etc.) in a water-miscible organic solvent (THF, dioxane,ethanol, methanol etc.).

(2) using an alkali mentioned above, in an alkanol (methanol, ethanoletc.) in anhydrous condition.

The reactions above are carried out generally at from -10° C. to 100° C.

In each reaction in the present invention, products may be purified byconventional manner. For example, it may be carried out by distillationat atmospheric or reduced pressure, high performance liquidchromatography, thin layer chromatography or column chromatography usingsilica gel or magnesium silicate, washing or recrystallization.Purification may be carried out after each reaction , or after a seriesof reactions.

Starting Materials

Starting materials and reagents in the present invention are knowncompounds per se or may be prepared by known methods per se.

For example, acids of the general formula (II) may be prepared by themethods described in the specification of Japanese Patent ApplicationKokai Nos. 60-97946, 60-116657 60-142941, 60-142936 or 60-146855.

A certain compound of the general formula (VIII) wherein R³ is ahydrogen atom is described in J. Med. Chem., 8, 446 (1965).

A certain compound of the general formula (XIII) wherein R³ is ahydrogen atom is described in J. Am. Chem. Soc., 75, 3277 (1953).

The compounds of the general formula (XV) may be prepared by the methoddescribed in J. Med. Chem., 20, 371 (1977).

A certain compound of the general formula (XXXI) wherein R³ is ahydrogen atom is described in J. Org. Chem., 42, 1925 (1977).

The compounds of the general formula (XXXXVIII) may be prepared from thecompounds of the general formula (II).

Compounds of the general formula (XXXXVI), (XXXXVII) and (XXXXVIII) areknown compounds per se, or may be prepared by known methods per se.

For example, compounds wherein B is a morpholine ring, compounds whereinB is 2,3,4,5tetrahydrofuran, compounds wherein B is a hydroxypyridinering, compounds wherein B is 3,4,5,6-tetrahydro-2H-pyran ring may beprepared by the methods described in J. O. Chem., 32, 4155 (1967), Chem.Abst. 98, 179352 q (1983), J. O. Chem., 32, 4155 (1967), and Chem.Abst., 84, 58747z, respectively or similar methods thereof.

Salts

The compounds of the present invention of the general formula (I) mayform salts at the carboxy or tetrazolyl moiety.

By converting into salts, solubility of the compounds of the presentinvention in water can be increased, and therefore may be more readilyadministered as pharmaceuticals.

The compounds of the present invention may easily be converted intocorresponding salts by the methods known per se, e.g. methods describedhereafter.

The salts in the present invention are preferably non-toxic ones. Thenon-toxic salts mean salts of cations that are relatively innocuous toliving body (animals including human beings) tissues and that theeffective pharmacological properties of the compounds of the generalformula (I) are not impaired by side effect(s) resulting from thecations when used in an amount required for the prevention and/ortreatment. And water-soluble salts are preferable.

Suitable salts include, for example, a salt of an alkali metal such assodium, potassium, a salt of an alkaline metal such as calcium,magnesium, an ammonium salt and a pharmaceutically acceptable(non-toxic) amine salt.

Amines suitable for forming such salts with carboxylic acid ortetrazolyl group are well known and include, for example, those amineswhich are theoretically obtained by substituting one or more of hydrogenatom(s) of ammonia by other group(s). These groups, which may be thesame or different when one or more hydrogen atom(s) are substituted, areselected from, for example, alkyl group(s) of from 1 to 6 carbon atom(s)and hydroxyalkyl group(s) of from 1 to 3 carbon atom(s). Suitablenon-toxic amine salts include salts of a tetraalkylammonium group, suchas tetramethylammonium salt and salts of an organic amine, such asmethylamine, dimethylamine, cyclopentylamine,benzylamine,phenethylamine, piperidine, monoethanolamine,diethanolamine, lysine and alginine.

Salts can be obtained from the compounds of the present invention of thegeneral formula (I), by methods known per se, for example, by reactingthe compound of the general formula (I) and a suitable base such as ahydroxide or carbonate of an alkali metal or alkaline earth metal,ammonium hydroxide, ammonia or an organic amine in theoretical amountsin an appropriate solvent.

The salts can be isolated by freeze-drying the solution, or byfiltration if the salts are sufficiently insoluble to the reactionsolution, or if necessary, by removing part of the solvent followed byfiltration.

Pharmaceutical Activities

The compounds of the present invention possess an antagonistic activityon leukotrienes, inhibitory activity on phospholipase, on 5α-reductaseand on aldose reductase.

In a standard laboratory test, for example, the compounds of the presentinvention showed the pharmaceutical activity in the following tables.

The compounds of the present invention showed an antagonistic activityon LTD₄ in vitro (method is described hereafter), shown in the followingtables.

                  TABLE I                                                         ______________________________________                                        Antagonistic activity of compounds of following                               general formula on LTD.sub.4                                                   ##STR38##                    (IA')                                           R                    IC.sub.50 (μM)                                        ______________________________________                                        alkyl                0.07-40                                                  alkoxy               0.009-0.9                                                alkenyloxy           0.0005-1.4                                               alkynyloxy           0.0002-0.013                                             alkylthio            0.17-17.5                                                alkoxy substituted by halogen atom                                                                 0.0004-0.007                                             cycloalkylalkoxy     0.08-0.2                                                 (alkyl)phenylalkoxy  0.0004-0.7                                               naphthylalkyl        0.008                                                    ______________________________________                                    

                  TABLE II                                                        ______________________________________                                        Antagonistic activity of compounds of following                               general formula on LTD.sub.4                                                   ##STR39##                   (IA")                                            R                    IC.sub.50 (μM)                                        ______________________________________                                        alkyl                0.1-1.6                                                  alkoxy               0.004-2.3                                                alkenyloxy           0.02-1.8                                                 alkynyloxy           0.4-0.5                                                  alkylthio            0.3-1.1                                                  alkoxy substituted by halogen atom                                                                 0.003-0.08                                               cycloalkyl           0.5                                                      cycloalkylalkoxy     0.09-1.5                                                 phenylalkoxy         0.009-0.7                                                ______________________________________                                    

                  TABLE III                                                       ______________________________________                                        Comparison of activity by alkylene chain change                                                           IC.sub.50                                         Formula                     (μM)                                           ______________________________________                                         ##STR40##                  2.6                                                ##STR41##                  8.3                                                ##STR42##                  0.66                                               ##STR43##                  0.074                                              ##STR44##                  15.5                                               ##STR45##                  20.0                                              ______________________________________                                    

As is obvious from the Tables-I and II, compounds of 1,4-benzodioxaneskelton having any substituent R, represented by the general formula(IA') or (IA") among the compounds of the present invention (i.e. thecase when B and R⁴ are fixed and R¹ and A are changed in the generalformula (I)) have enough activity for pharmaceutical use.

From Table III, it is confirmed that if the alkylene moiety(corresponding to A in general formula (I)) is converted, compoundshaving sufficient pharmaceutical activity are obtained.

In the following tables, the comparision of activity by skeletonstructure changes are shown.

                  TABLE IV                                                        ______________________________________                                        Comparison of activity by skeleton structure change (1)                                                   IC.sub.50                                         Formula                     (μM)                                           ______________________________________                                         ##STR46##                  0.37                                               ##STR47##                  0.03                                               ##STR48##                  0.69                                              ______________________________________                                    

                  TABLE V                                                         ______________________________________                                        Comparison of activity by skeleton structure change (2)                       Formula                    IC.sub.50 (μM)                                  ______________________________________                                         ##STR49##                 2.6                                                 ##STR50##                 0.18                                                ##STR51##                 1.2                                                ______________________________________                                    

                  TABLE VI                                                        ______________________________________                                        Comparison of activity by skeleton structure change (3)                       Example      Symbol                                                           No.          B           IC.sub.50 (μM)                                    ______________________________________                                        1 (501)                                                                                     ##STR52##  0.076                                                1 (505)                                                                                     ##STR53##  0.205                                                1 (514)                                                                                     ##STR54##  0.0046                                               1 (516)                                                                                     ##STR55##  0.0026                                               1 (518)                                                                                     ##STR56##  0.033                                                1 (521)                                                                                     ##STR57##  0.0013                                               ______________________________________                                    

And further, from Tables IV, V and VI, it is clear that compounds inwhich the basic structural skeleton contains various rings also possesssufficient activity compared with the compounds having a1,4-benzodioxane skeleton (i.e., when R¹ and A are fixed and B and R⁴are changed).

According to the points above described, it is estimated fairly thatreplacement of an essential skeleton structure of a certain compoundfrom 1,4-benzodioxane to various rings and/or change of the groups ofgeneral formula: R¹ --A-- in the general formula (I) also leads to acompound having enough activity for pharmaceutical use.

From these data, it is fully expected that the full scope of the presentinvention has effective activity and therefore is useful as apharmaceutical agent.

Antagonistic activity of the compounds of the present invention on LTD₄were measured by the following method.

A segment of ilem (2.5 cm) was removed from guinea pig 300-400 g andsuspended in a Magnus tube containing Tyrodes solution. The tube wasmaintained at 37° C. and aerated with 95% O₂ -5% CO₂. After stabilizingfrom 30 mins, 5×10⁻⁹ g/ml of LTD₄ was added to the Magnus tube.Contraction length at the time and contraction lengths when thecompounds of the present invention were challenged at someconcentrations were measured, and the IC₅₀ value were calculated.

(2) Inhibitory activity on 5α-reductase in vitro

The compounds of the present-invention showed an inhibitory activity on5α-reductase in vitro (method is described hereafter), shown in thefollowing table.

                  TABLE VII                                                       ______________________________________                                        Inhibitory activity on 5α-reductase                                            Example                                                                       No.    IC.sub.50 (μM)                                               ______________________________________                                               4(204) 2                                                                      4(206) 4                                                                      6(1)   5                                                               ______________________________________                                    

Inhibitory activity of the compounds of the present invention on5α-reductase was measured by the following method.

Inhibitory activity of the compounds of the present invention on5α-reductase (IC₅₀) in vitro was measured by the following method.

Compounds tested were incubated with radioactive [4-¹⁴ C]testosterone (5μM) and NADPH (5×10⁻³ M) in the medium containing 5α-reductase, 0.09MHepes (pH 7.4) and 0.22M sucrose at 37° C. for 60 mins. The reaction wasstopped by adding solution of chloroform-methanol (1:2). The reactionmixture was centrifuged and the supernatant was separated by thin layerchromatography on silica gel using chloroform-methanol-acetic acid(99.2:0.6:0.2) as a developing solvent. Radioactivity of formed5α-dihydrotestosterone was measured by TLC scanner. The values of IC₅₀were determined by the inhibition percents of 5α-reductase activitymeasured by the above procedure (see Endocrinal, Japon., 18, 179(1971).).

Toxicity

On the other hand, it was confirmed that the acute toxicity (LD₅₀) overthe full scope of the present invention was more than 500 mg/kg animalbody weight by intravenous administration. Therefore, the compounds ofthe present invention may be considered to be sufficiently safe andsuitable for pharmaceutical use.

For example, the values of LD₅₀ of the compounds prepared in Examples1(76), 1(212), 1(230) and 1(247) were more than 1000 mg/kg animal bodyweight by intravenous administration in male mice weighing 170-180 g,respectively.

Application for Pharmaceuticals

The present invention is also related to methods of use as a leukotrieneantagonist, phospholipase inhibitor, 5α-reductase inhibitor and/oraldose reductase inhibitor.

Suppressing leukotrienes is useful for the prevention and/or treatmentof tracheal, bronchial or lung diseases such as asthma, allergic lungdiseases, allergic shock or various allergic diseases in mammalsincluding human beings, especially human beings.

Inhibiting phospholipases (phospholipase A₂ and/or phospholipase C) isuseful for the prevention and/or treatment of diseases induced by themetabolites of arachidonic acid including leukotrienes described above,e.g. thrombosis such as thrombosis induced by damage of cerebral orcoronary, endothelium or intina and inflammations such as arthritis,rheumatism in mammals including human beings, especially human beings.

Inhibiting 5α-reductase is useful for the prevention and/or treatment ofprostatic hypertrophy, male pattern baldness or ache in mammalsincluding human beings, especially human beings.

Inhibiting aldose reductases is useful for the prevention and/ortreatment of diabetic complications e.g. retinopathy, diabetic cataract,nerve disturbances or renal disorders.

For the purposes hereinbefore described, the compounds of the presentinvention of the general formula or non-toxic salts thereof may normallybe administered systemically or partially; usually by oral or parenteraladministration.

The doses to be administered is determined depending upon age, bodyweight, symptom, the desired therapeutic effect, the route ofadministration, and the duration of the treatment etc. In the humanadult, the doses per person per dose are generally between 0.1 mg and100 mg, preferably between 2 mg and 20 mg, by oral administration, up toseveral times per day, and between 10 ug and 10 mg, preferably between0.1 mg and 1 mg, by parenteral administration up to several times perday.

As mentioned above, the doses to be used depend upon various conditions.Therefore, there are cases in which doses lower than or greater than theranges specified above may be used.

Solid compositions according to the present invention for oraladministration include compressed tablets, dispersible powders andgranules. In such solid compositions, one or more of the activecompound(s) is or are, admixed with at least one inert diluent such aslactose, mannitol, glucose, hydroxypropylcellulose, microcrystallinecellulose, starch, polyvinylpyrrolidone or magnesium metasilicatealuminate. The compositions may also comprise, as is normal practice,additional substances other than inert diluents e.g. lubricating agentssuch as magnesium stearate, disintegrating agents such as cellulosecalcium gluconate, and assistant for dissolving e.g. arginine, glutamicacid or amino-acid such as aspartic acid. The tablets or pills may, ifdesired, be made into gastric film-coated or enteric film-coated tabletsor pills, such as sugar-coated, gelatin-coated, hydroxypropylcellulose-coated or hydroxypropylmethyl cellulose phthalate-coatedtablets or pills; two or more of layers may be used. The compositionsfor oral administration also include capsules of absorbable materialsuch as gelatin.

Liquid compositions for oral administration includepharmaceutically-acceptable emulsions, solutions, suspensions, syrupsand elixirs containing inert diluents commonly used in the art such asdistilled water or ethanol. Besides inert diluents such compositions mayalso comprise adjuvants such as wetting and suspending agents, andsweetening, flavoring, perfuming and preserving agents.

Other compositions for oral administration include spray compositionswhich may be prepared by known methods and which comprise one or more ofthe active compound(s).

Preparations for injection according to the present invention forparenteral administration include sterile aqueous or non-aqueoussolutions, suspensions or emulsions. Examples of aqueous solvents orsuspending media are distilled water for injection and physiologicalsalt solution. Examples of non-aqueous solvents or suspending media arepropylene glycol, polyethylene glycol, vegetable oils such as olive oil,alcohols such as ethanol, POLYSORBATE 80 (registered Trade Mark). Thesecompositions may also include adjuvants such as preserving, wetting,emulsifying, despersing agents and assistant agent for dissolving (e.g.arginine, glutamic acid or amino-acid such as aspartic acid). They maybe sterilized, for example, by filtration through a bacteria-retainingfilter, by incorporation of sterilizing agents in the compositions or byirradiation. They may also be manufactured in the form of sterile solidcompositions which can be dissolved in sterile water or some othersterile injectable medium-immediately before use.

Other compositions for parenteral administration include liquids forexternal use, and endermic liniments such as ointments, suppositoriesand pessaries which comprise one or more of the active compound(s) andmay be prepared by known methods.

Nomenclature and excluding compounds

Throughout the specification including claims, the compounds of thepresent invention are named as derivatives having the following fusedbenzene rings or benzene ring. ##STR58##

And throughout the specification including claims, isomers generated bythe existence of stereo configuration unlimited (e.g. asymmetric carbon,double bond) are included in the corresponding formula, respectively.

However, compounds which do not normally exist for chemical or physicalreasons according to general chemical knowledge are excluded from thepresent invention, e.g. certain compounds having a multiple bondadjacent to an oxygen, nitrogen or sulphur atom.

REFERENCE EXAMPLES AND EXAMPLES

The following reference examples and examples illustrate the presentinvention, but should not be construed as limiting the presentinvention.

In the reference examples and examples, "TLC", "NMR", "IR" and "Mass"represent "Thin layer chromatography", "Nuclear magnetic resonancespectrum", "Infrared absorption spectrum" and "Mass spectrum",respectively.

The solvents in the parentheses show the developing or eluting solventsandthe ratios of the solvents used are by volume in chromatographicseparations.

Unless otherwise specified, "IR" was measured by the KBr tablet methodand "NMR" was measured in a mixture of chloroform-d and ethanol-d₄respectively.

REFERENCE EXAMPLE 1

Synthesis of 3- (m-methoxy-p-pentyloxycinnamoyl)aminopyrocatechol##STR59##

Oxyalyl chloride (4.5 ml) was added to m-methoxy-p-pentyloxybenzoic acid(528 mg). In an atmosphere of argon, the solution was stirred for 30 minat room temperature and then concentrated under reduced pressure. Theresidue was dissolved into methylene chloride (10 ml). In an atmosphereofargon, the solution was dropped to a solution of 3-aminopyrocatechol(275 mg) in a mixture of methylene chloride (10 ml) and pyridine (3 ml)coolingwith ice, and the solution was stirred for 1 hr at the sametemperature. After stirring for 2 hrs at room temperature, the solutionwas poured into1N hydrochloric acid. The mixture was extracted withethyl acetate. The extract was washed with water and a saturated aqueoussolution of sodium chloride, successively, dried and concentrated underreduced pressure. Solids obtained was washed with hexane, and dried togive the title compound (700 mg) having the following physical data:

TLC: Rf 0.20 (ethyl acetate: hexane=1:2); NMR (CDCl₃): δ10.00 (1H, s),7.75 (1H, d), 7.60 (1H, s), 6.30-7.25(7H, m), 6.10(1H, s), 4.10(2H, t),1.90(3H, s); Mass: m/e 371(M⁺), 247, 177, 145, 125, 117,

REFERENCE EXAMPLE 2

Synthesis of8-(m-methoxy-p-pentyloxycinnamoyl)-amino-1,4-dioxane-2-carbonitrile##STR60##

Dry potassium carbonate (770 mg) and 2-chloroacrylonitrile (0.30 ml)were added to a solution of3-(m-methoxy-p-pentyloxycinnamoyl)aminopyrocatechol(690 ml; synthesizedin reference example 1) in acetone (10 ml). In an atmosphere of argon,the mixture was refluxed for 3 hrs. The reaction mixture cooled to roomtemperature was poured into ice-water (50 ml). The mixture was extractedwith ethyl acetate. The extract was dried, and concentrated underreduced pressure. The residue was purified by column chromatography onsilica gel (methylene chloride: ethyl acetate=10:1) to give the titlecompound (565 mg) having the following physical data:

TLC: Rf 0.15 (ethyl acetate: hexane=1:2); NMR (CDCl₃): δ8.25 (1H, dd),7.70 (1H, d), 7.55 (1H, s), 7.00-7.25(2H, m), 6.90(1H, d), 6.85(1H, d),6.70 (1H, dd), 6.45 (1H, d), 5.20 (1H, dd), 4.30-4.55(2H, m),4.05(2H,t), 3.93(3H, s); Mass: m/e 422(M⁺), 247, 177, 145, 117.

REFERENCE EXAMPLE 3 (EXAMPLE A)

Synthesis of 8-(p-pentylcinnamoyl)amino-1,4-benzodioxane-2-acetic acidmethyl ester ##STR61##

Potassium carbonate (509 mg) was added to a solution of3-(p-pentylcinnamoyl)aminopyrocatechol (300 mg; synthesized by the sameprocedure as reference example 1) and 4-bromo-2-butenoic acid methylesterin acetone (10 ml), and the mixture was refluxed for 10 min. Thereaction mixture was poured into water. The mixture was extracted withethyl acetate. The extract was purified by column chromatography onsilica gel (hexane: ethyl acetate=5:1) to give the title compound (341mg) .

REFERENCE EXAMPLE 4

Synthesis of 8-(p-pentylcinnamoyl)amino-1,4-benzodioxane-2-acetamide##STR62##

8-(p-pentylcinnamoyl)amino-l,4-benzodioxane-2-acetic acid methyl ester(341mg; synthesized in reference example 3) was dissolved into ethanolwhich was saturated with ammonia (20 ml). The solution was allowed tostand for 3 days at 100° C. The reaction mixture was concentrated underreduced pressure. The residue was purified by column chromatography onsilica gel (hexane: ethyl acetate=2:1) to give the title compound (191mg).

REFERENCE EXAMPLE 5

Synthesis of 8-(p-pentylcinnamoyl)amino-1,4-benzodioxane-2acetonitrile##STR63##

Trifluoroacetic anhydride (0.1 m) was added to a solution of8-(p-pentylcinnamoyl)amino-1,4-benzodioxane-2-acetamide (191 mg;synthesized in reference example 4) in THF (10 ml) cooling with ice. Andpyridine (0.02 ml) was added the mixture. After stirring for 10 min, themixture was poured into water. The mixture was extracted with ethylacetate. The extract was dried, concentrated under reduced pressure togive the title compound.

EXAMPLE 1

Synthesis of 8-[p-(3Z-hexenyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane ##STR64##

A mixture of p-(3Z-hexenyloxy)benzoic acid (110 mg) and oxalyl chloride(1 ml) was stirred for 1 hr at room temperature. From the mixture,excess oxalyl chloride was removed under reduced pressure. The residuewas dried in vacuo, and then dissolved into methylene chloride (2 ml).In an atmosphere of argon, the solution was dropped into a solution of8-amino-2-(5-tetrazolyl)-1,4-benzodioxane hydrochloride (128 mg) in amixture of methylene chloride (2 ml) and pyridine (0.7 ml). The solutionwas stirred for 5 hrs at room temperature. The solution was diluted withethyl acetate. The diluted solution was poured into 1N hydrochloric acid(1 ml). The mixture was extracted with ethyl acetate. The extract waswashed with water, dried, and concentrated under reduced pressure. Theresidue was recrystallized from benzene to give the title compound (112mg) having the following physical data:

TLC: Rf 0.57 (chloroform: methanol=3:1); NMR: δ7.90 (2H, d), 7.88 (1H,m), 7.46 (1H, dd), 6.96 (2H, d), 6.92 (1H, t), 6.78 (1H, dd), 5.77 (1H,dd), 5.70 (2H, m), 4.61 (2H, m), 4.04 (2H, t), 2.57 (2H, dt), 2.12 (2H,m), 1.01 (3H, t); IR: ν3600-2300, 1650, 1610, 1540, 1505, 1460, 1250,1175, 1090, 840,770 cm⁻¹ ; Mass: m/e 421(M⁺), 203; Appearance: whitepowder.

Example 1(1)-1(121)

By the same procedure as example 1, using with a correspondingcarboxylic acid and 8-amino-2-(5-tetrazolyl)-1,4-benzodioxanehydrochloride, following compounds having the following physical data,shown in table [VIII] were given ##STR65##

    TABLE VIII        Substituent R Rf value in TLC     Example in the general (developing     No. formula (Im) solvent) NMR (δppm) IR (νcm.sup.-1) Mass     Appearance              1(1)      0.51(methylenechloride:methanol =3:1) 7.87(2H, d), 7.50(1H, dd),     6.92(1H, t),6.77(1H, dd), 5.80(1H, dd), 4.68-4.54(2H, m), 2.68(2H, t),     1.74-1.54(2H, m),1.50-1.20(4H, m), 0.99(3H, t) 3400-2400, 1640,1610,     1540, 1460 393(M.sup.+).243,175 whitepowder       1(2)            ##STR66##      0.52(methylenechloride:methanol =4:1) 7.83(2H, d), 7.49(1H, dd),     7.33(2H, d),6.91(1H, t), 6.75(1H, dd), 5.76(1H, dd),4.60(2H, m),     2.98(2H, t), 1.70(2H, m),1.39(4H, m), 0.90(3H, t) 3600˜2300,     1635 1620, 1595, 1545,1460, 1340, 1280,1265, 1100, 780 425, 207 whitepowd     er       1(3)            ##STR67##      0.47(methylenechloride:methanol =4:1) 7.68(1H, d), 7.46(2H, d),     7.26(2H, d),6.89(1H, t), 6.73(1H, dd), 6.72(1H, d),5.71(1H, dd),     4.68(1H, dd), 4.49(1H, dd),2.96(2H, t), 1.68(2H, m), 1.39(4H, m),0.90(3H,      t) 3600-2300, 1660,1620, 1595, 1545,1460, 1265, 1200,1090, 970, 820     451(M.sup.+) 233 paleyellowcrystal       1(4)            ##STR68##      0.51(methylenechloride:methanol =17:3) 7.69(2H, m), 7.53(2H, d),     6.98(2H, d),6.90(1H, t), 6.73(1H, dd), 6.58(1H, d),5.71(1H, dd),     4.70(3H, m), 4.48(1H, dd),2.24(2H, m), 1.14(3H, t) 3600-2200, 1640,1605,     1530, 1510,1450, 1260, 1170,995, 820 431(M.sup.+)219, 213 yellowpowder     1(5)      ##STR69##      0.40(methylenechloride:methanol =17:3) 7.69(2H, m), 7.50(2H, d),     6.90(1H, t),6.89(2H, d), 6.72(1H, dd), 6.62(1H, d),5.72(1H, dd),     4.67(1H, dd), 4.49(1H, dd),3.98(2H, t), 1.79(2H, m), 1.36(6H, m),0.90(3H,      t) 3600-2100, 1640,1600, 1530, 1500,1440, 1255, 1190,1160, 1090,     960,815, 760, 700 449(M.sup.+)231, 219 whitepowder       1(6)            ##STR70##      0.26(chloroform:methanol =3:1) (CDCl.sub.3)8.23(1H, s), 7.79(2H, d),     7.22(2H, d), 7.05(1H, d), 6.84(1H, t), 6.72(1H, d), 5.69(1H, m),4.74(1H,     dd), 4.46(1H, dd), 2.64(2H, t), 1.60(2H, m), 1.15-1.45(12H, m), 0.87(3H,     t) 2930, 2860, 2740,1635, 1610, 1540,1450, 1325, 1275,1090, 1040,     900,850, 770, 715, 595 449(M.sup.+)299, 231,145, 131,118, 91 whitepowder       1(7)            ##STR71##      0.26(chloroform:methanol =3:1) (CDCl.sub.3)8.12(1H, s), 7.81(2H, d),     7.25(2H, d), 7.02(1H, d), 6.85(1H, t), 6.75(1H, d), 5.72(1H, m),4.80(1H,     dd), 4.47(1H, dd), 2.66(2H, t), 1.60(2H, m), 1.15-1.45(14H, m), 0.87(3H,     t) 2930, 2860, 1604,1620, 1605, 1540,1470, 1335, 1285,1270, 1100,     1050,920, 780 463(M.sup.+)313, 245,131, 118,91, 69 whitepowder   1(8)      ##STR72##      0.26(chloroform:methanol =4:1) (CDCl.sub.3)7.94(1H, s), 7.84(2H, d),     7.30(2H, d), 6.70-7.00(3H, m), 5.76(1H, m), 4.92(1H, dd), 4.50(1H, dd),     2.68(2H, t), 1.63(2H, m), 1.15-1.45(16H, m), 0.88(3H, t) 2930, 2850,     1640,1615, 1545, 1460,1330, 1280, 1265,1095, 775 477(M.sup.+)327,     259,131, 118,91 whitepowder       1(9)            ##STR73##      0.26(chloroform:methanol =4:1) (CDCl.sub.3)7.97(1H, s), 7.84(2H, d),     7.28(2H, d),6.70-7.00(3H, m), 5.74(1H, m), 4.90(1H,dd), 4.49(1H, dd),     2.68(2H, t), 1.63(2H,m), 1.15-1.45(18H, m) 2930, 2850, 1640,1615, 1545,     1460,1335, 1280, 1265,1090, 775, 491(M.sup.+)341, 273,131, 118,91     whitepowder       1(10)            ##STR74##      0.46(chloroform:methanol =3:1) 7.70(2H, m), 7.54(2H, d), 6.94(2H,     d),6.91(1H, t), 6.74(1H, dd), 6.68(1H, d),6.05(1H, m), 5.74(1H, dd),     5.38(2H, m),4.70(1H, dd), 4.59(2H, d), 4.51(1H, dd) 3600-2200, 1650,1605,      1540, 1510,1455, 1260, 1200,1170, 1100, 1020, 980,960, 820, 780, 715     405(M.sup.+)219, 187 yellowpowder       1(11)            ##STR75##      0.45(chloroform: methanol =3:1) 7.71(2H, m), 7.56(2H, d), 6.94(3H,     m),6.77(1H, m), 6.72(1H, d), 5.79(1H, m),4.72(1H, dd), 4.03(2H, m),     1.82(2H, m),1.35(8H, m), 0.92(3H, m) 3600-2200, 16501595, 1440, 1260,1170     , 1090, 960,820 463(M.sup.+)245, 231,219 yellowpowder       1(12)            ##STR76##      0.39(chloroform:methanol =3:1) 7.89(2H, d), 7.46(1H, dd), 6.88(2H,     d),6.81(1H, t), 6.75(5H, dd), 5.77(1H, dd),4.62(2H, m), 4.04(2H, t),     1.80(2H, m),1.51(2H, m), 0.90(3H, t) 3600-2300, 1630,1600, 1540,     1500,1450, 1250, 1170,1085, 840, 770 395(M.sup.+)177 whitepowder   1(13)      ##STR77##      0.46(chloroform:methanol =3:1) 7.89(2H, m), 7.46(1H, dd), 6.96(2H,     d),6.92(1H, t), 6.76(1H, dd), 5.76(1H, dd),4.62(2H, m), 4.02(2H, t),     1.81(2H, m),1.26(10H, m), 0.88(3H, t) 3600-2300, 1630,1605, 1540,     1505,1460, 1260, 1180,1090, 840, 770 465(M.sup.+)247 whitepowder   1(14)      ##STR78##      0.42(chloroform:methanol =3:1) 7.72(1H, d), 7.64(1H, m), 7.48(2H,     d),7.36(2H, s), 7.22(6H, m), 6.90(1H, t),6.73(1H, dd), 6.72(1H, d),     5.70(1H, dd),4.67(1H, dd), 4.49(1H, dd), 3.99(2H, s) 3600-2300, 1640,1600     , 1540, 1450,1255, 1200, 1090,970, 960, 730,690 439(M.sup.+)259, 221     whitepowder       1(15)            ##STR79##      0.44(chloroform:methanol =3:1) 7.72(1H, d), 7.66(1H, m), 7.49(2H,     d),7.23(2H, d), 6.90(1H, t), 6.75(1H, d),6.74(1H, dd), 5.72(1H, dd),     4.68(1H, dd),4.49(1H, dd), 2.53(1H, m), 1.86(5H, m),1.40(5H, m) 3600-2300     , 1650,1600, 1540, 1480,1455, 1260, 1210,1090, 980, 960,820, 690     431(M.sup.+)219, 213 yellowpowder       1(16)            ##STR80##      0.30(chloroform:methanol =5:1) 7.74(1H, d), 7.48(2H, d), 6.88(2H,     d),6.88(1H, t), 6.74(1H, dd), 7.44(1H, s),5.72(1H, t), 4.62(2H, d),     4.01(2H, t) 1660, 1610, 1580,1540, 1515, 1460, 435(M.sup.+)217 whitepowde     r       1(17)            ##STR81##      0.30(methylenechloride:methanol =5:1) 7.40(2H, d), 7.36(1H, d),     7.18(2H, d),6.89(1H, t), 6.74(1H, dd), 6.27(1H, d),5.74(1H, t), 4.72-4.50     (2H, m) 3300, 3200-2300,1660, 1610, 1540,1460 433(M.sup.+)215 whitepowder       1(18)            ##STR82##      0.48(chloroform:methanol =3:1) 7.69(1H, d), 7.63(1H, m), 7.51(2H,     d),6.90(2H, d), 5.90(1H, m), 5.72(1H, dd),5.16(2H, m), 4.68(1H, dd),     4.49(1H, dd),4.04(2H, t), 2.56(2H, dt) 3600-2300, 1650, 1600, 1540,      1     1505,450, 1255, 1200,1170, 1095, 1020,960, 820 419(M.sup.+)219, 201     paleyellowpowder       1(19)            ##STR83##      0.51(chloroform:methanol =3:1) 7.69(1H, d), 7.64(1H, m), 7.51(2H,     d),6.90(1H, t), 6.89(2H, d), 6.73(1H, dd),6.63(1H, d), 5.72(1H, dd),     4.68(1H, dd),4.50(1H, dd), 3.98(2H, t), 1.80(2H, m),1.62(1H, m),     1.36(2H, m), 0.92(6H, d) 3600-2200, 1650,1600, 1540, 1505,1450, 1260,     1165,1095, 960, 820 419(M.sup.+)231, 219 whitepowder       1(20)            ##STR84##      0.26(chloroform:methanol =3:1) (CDCl.sub.3)7.75-7.95(3H, m), 6.70-7.05(5     H, m),5.76(1H, m), 4.98(1H, dd), 4.50(1H, dd),3.99(2H, t), 1.85(2H, m),     1.06(3H, t) 2970, 2870, 2730,1630, 1600, 1540,1505, 1460, 1330,1280,     1255, 1175,1100, 840, 780 381(M.sup. +)231, 163,121, 93,65 whitepowder     1(21)      ##STR85##      0.26(chloroform:methanol =3:1) (CDCl.sub.3)7.94(1H, s), 7.87(2H, d),     6.70-7.10(5H,m), 5.75(1H, m), 4.88(1H, dd), 4.50(1H,dd), 4.01(2H, t),     1.82(2H, m), 1.20-1.60(6H, m), 0.92(3H, t) 3420, 2930, 2860,1635, 1605,     1540,1505, 1460, 1255,1175, 1090, 840,775 423(M.sup.+)395, 273,205,     177,121 whitepowder       1(22)            ##STR86##      0.26(chloroform:methanol =3:1) (CDCl.sub.3)7.80-8.00(2H, m), 6.70-7.05(5     H, m), 5.74(1H, m), 4.90(1H, dd), 4.49(1H, dd),4.00(2H, t), 1.80(2H, m),     1.15-1.70(8H,m), 0.89(3H, t) 3420, 2930, 2860,1640, 1605, 1550,1510,     1460, 1260,1180, 1100, 845,775 437(M.sup.+)287, 219,121, 93 whitepowder      1(23)      ##STR87##      0.26(chloroform:methanol =3:1) (CDCl.sub.3)7.75-8.00(3H, m), 6.70-7.05(5     H, m), 5.74(1H, m), 4.90(1H, dd), 4.48(1H, dd),4.00(2H, t), 1.80(2H, m),     1.10-1.60(10H, m), 0.88(3H, t) 3430, 3320, 2930,2850, 2730, 1635,1605,     1545, 1505,1460, 1320, 1255,1180, 1090, 840, 770 451(M.sup.+)396,     301,233, 121,93 whitepowder       1(24)            ##STR88##      0.26(chloroform:methanol =3:1) (CDCl.sub.3)7.75-8.00(3H, m), 6.70-7.05(5     H, m),5.76(1H, m), 4.94(1H, dd), 4.50(1H, dd),4.02(2H, t), 1.80(2H, m),     1.10-1.70(14H, m), 0.88(3H, t) 3420, 2930, 2850,1640, 1610, 1545,1510,     1460, 1260,1180, 1100, 845,775 479(M.sup.+)261, 121,93 whitepowder     1(25)      ##STR89##      0.26(chloroform:methanol =3:1) (CDCl.sub.3)7.94(1H, s), 7.86(2H, d),     6.70-7.10(5H, m), 5.74(1H, m), 4.87(1H, dd),4.48(1H, dd), 4.04(2H, t),     1.60-1.95(3H, m), 0.98(4H, d) 3420, 2960, 2870,1635, 1605, 1540,1505,     1460, 1260,1180, 1100, 840,775 409(M.sup.+)191, 121,93 whitepowder     1(26)      ##STR90##      0.26(chloroform:methanol =3:1) (CDCl.sub.3)7.88(2H, d), 7.83(1H, s),     6.75-7.10(5H,m), 5.76(1H, m), 4.96(1H, dd), 4.50(1H,dd), 4.01(2H, t),     1.20-1.95(5H, m),0.93(6H, d) 3420-2960, 2870,1640, 1610, 1545,1510,     1460, 1260,1180, 1100, 845775 423(M.sup.+) 381, 205,161, 121,93 whitepowd     er       1(27)            ##STR91##      0.53(chloroform:methanol =3:1) 7.48(2H, m), 7.32(2H, d), 6.82(4H,     m),6.75(1H, t), 6.65(1H, dd), 6.14(1H, d),5.63(1H, dd), 4.59(1H, dd),     4.42(1H, dd),3.86(2H, t), 1.74(2H, m), 0.97(3H, t) 3600-2300, 1650,1600,     1440, 1250,1160, 1120, 1090,980, 830, 760 433(M.sup.+)215 yellowpowder     1(28)      ##STR92##      0.49(chloroform:methanol =3:1) 7.58(2H, m), 7.39(2H, d), 7.27(2H,     d),6.92(3H, m), 6.74(1H, dd), 6.28(1H, d),5.72(1H, dd), 4.68(1H, dd),     4.51(1H, dd),2.62(2H, t), 1.60(2H, m), 1.36(2H, m),0.94(3H, t) 3600-2200,      1650,1600, 1530, 1440,1260, 1095, 990,835 431(M.sup.+)219,213 yellowpowd     er       1(29)            ##STR93##      0.30(methylenechloride:methanol =5:1) 7.89(2H, d), 7.23(1H, dd),     6.96(2H, d), 6.90(1H, t), 6.77(1H, dd), 6.02-5.80,(1H, m), 5.80-5.74(1H,     m), 5.26-5.08,(2H, m), 4.84-4.50(2H, m) 3500-2300, 1635,1605, 1540,      1     1505,455, 1250 393(M.sup.+)191, 175 whitepowder       1(30)            ##STR94##      0.65(chloroform:methanol =3:1) 7.70(1H, d), 7.61(1H, m), 7.51(2H,     d),6.90(1H, t), 6.89(2H, d), 6.73(1H, dd),6.64(1H, d), 5.72(1H, dd),     5.50(2H, m),4.68(1H, dd), 4.50(1H, dd), 4.00(2H, t),2.55(2H, m),     2.10(2H, m), 1.00(3H, t) 3600-2100, 1650,1600, 1500, 1440,1250, 1160,     1090,1010, 960, 820 477(M.sup.+)229, 219 yellowpowder       1(31)            ##STR95##      0.40(methylenechloride:methanol =4:1) 7.31(1H, d), 7.48(1H, d),     7.48(2H, d),6.89(1H, t), 6.87(2H, d), 6.74(1H, dd),6.56(1H, d), 5.80-5.68     (1H, m),4.70-4.30(3H, m), 1.30(3H, d) 3500-2300, 1660, 1605, 1540,     1515,1460, 1260 435(M.sup.+)217 paleyellowpowder       1(32)            ##STR96##      0.61(chloroform:methanol =3:1) 7.72(1H, d), 7.62(1H, m), 7.51(2H,     d),6.92(2H, d), 6.91(1H, t), 6.74(1H, dd),6.62(1H, d), 5.68(3H, m),     4.60(4H, m),2.18(4H, m), 2.18(2H, m), 1.04(3H, t) 3600-2200, 1645,1600,     1540, 1505,1450, 1260, 1165,1100, 820 501,433(M.sup.+)287, 219,215       p     yellowowder       1(33)            ##STR97##      0.42(chloroform:methanol =3:1) 7.87(2H, d), 7.38(1H, dd), 6.93(2H,     d),6.90(1H, t), 5.75(1H, dd), 4.68(1H, dd),4.55(1H, dd), 4.46(1H, m),     1.72(2H, m),1.46(2H, m), 1.31(3H, d), 0.94(3H, t) 3600-2300, 1630,1600,     1540, 1500,1455, 1250, 1180,1100, 840, 770 409(M.sup.+)219, 191 whitepowd     er       1(34)            ##STR98##      0.44(chloroform:methanol =3:1) 7.92(2H, d), 7.45(1H, dd), 7.05(2H,     d),6.92(1H, t), 6.77(1H, dd), 5.76(1H, dd),4.75(2H, t), 4.64(2H, m),     2.22(2H, m),1.50(2H, m), 1.32(4H, m), 0.88(3H, t) 3600-2200, 1635,1600,     1540, 1500,1450, 1260, 1220,1170, 1080, 990,835, 760 447(M.sup.+)229,     219 paleyellowpowder       1(35)            ##STR99##      0.46(chloroform:methanol =3:1) 7.90(2H, d), 7.45(1H, dd), 6.98(2H,     d),6.92(1H, t), 6.76(1H, dd), 5.76(1H, dd),5.69(2H, m), 4.64(4H, m),     2.14(2H, m),1.40(2H, m), 1.32(4H, m), 0.89(3H, t) 3600-2300, 16301600,     1550, 1450,1240, 1165, 1080,830, 760 449(M.sup.+)329, 231219 paleyellowso     lid       1(36)            ##STR100##      0.10(chloroform:methanol =4:1) (CDCl.sub.3)7.80-8.00(3H, m), 7.32(2H,     d), 719(2H, d), 6.70-7.10(5H, m), 5.74(1H, m),5.08(2H, s), 4.89(1H, dd)     3420, 2930, 2850,1630, 1605, 1540,1500, 1455, 1245,1170, 1090, 840,770     485(M.sup.+)399, 365, 339, 267253, 219,147, 131 whitepowder   1(37)      ##STR101##      0.35(methylenechloride:methanol =(5:1) 7.90(2H, d), 7.34(1H, dd),     6.98(2H, d),6.92(1H, t), 6.78(1H, dd), 6.00-5.60(3H, m), 4.80-4.50(4H,     m) 3400, 3200-23001630, 1595, 1540,1500, 1450, 1240 463(M.sup.+)343,     2     245,19, 121 palebrownpowder       1(38)            ##STR102##      0.30(methylenechloride:methanol = 5:1) 7.73(1H, d), 7.49(2H, d),     6.90(2H, d),6.90(1H, t), 6.75(1H, dd), 6.58(1H, d),6.00-5.60(3H, m),     4.70-4.40(4H, m) 3350, 3100-23001650, 1595, 1530,1500, 1450, 1260     489(M.sup.+)379, 343,271 whitepowder       1(39)            ##STR103##      0.40(benzene:dioxan:acetic acid =20:10:1) 7.9(2H, d), 7.5-7.3(1H, m),     7.0-6.7(4H,m), 5.78(1H, m), 4.7-4.5(2H, m), 3.8(2H, m), 2.0-1.6(6H, m),     1.4-1.0(5H,m) 2920, 2850, 1620,1600 435(M.sup.+)217 whitepowder   1(40)      ##STR104##      0.4(benzene:dioxan:acetic acid =20:10:1) 7.9(2H, d), 7.5-7.3(1H, m),     7.0-6.7(4H,m), 5.75(1H, m), 4.8-4.5(2H, m),4.0(2H, t), 3.55(2H, t),     1.8(4H, s),1.5(4H, s) 2950, 2850, 1630,1600, 1460, 1250 457(M.sup.+) 239 w     hitepowder       1(41)            ##STR105##      0.4(benzene:dioxan:acetic acid =20:10:1 7.9(2H, d), 7.5-7.3(1H, m),     7.0-6.7(4H, m),5.75(1H, m), 4.8-4.5(2H, m), 4.05(2H, t),3.65(2H, t),     1.85(4H, s), 1.7(2H, s) 2950, 2850, 1630,1600, 1460, 1250 443(M.sup.+)225      whitepowder       1(42)            ##STR106##      0.4(benzene:dioxan:acetic acid =20:10:1) 7.9(2H, d), 7.5-7.3(1H, m),     7.0-6.7(4H, m),5.78(1H, m), 4.8-4.5(2H, m), 4.1(2H, s),3.65(2H, s),     2.6(4H, s) 1670, 1640, 1490,1290      ##STR107##      whitepowder       1(43)            ##STR108##      0.10(chloroform:methanol =4:1) 7.98(1H, d), 7.82(1H, dd), 7.28(1H,     m),7.00(1H, d), 6.90(1H, t), 6.78(1H, dd),5.60-6.00(3H, m), 4.45-4.85(4H,      m),2.10(2H, m), 1.20-1.50(6H, m),0.88(3H, t) 2930, 2860, 1640,1615,     1600, 1545,1500, 1460, 1270,1100, 1060, 980,780 483(M.sup.+)373,     329,265, 219,155, 149 whitepowder       1(44)            ##STR109##      0.4(benzene:dioxan:acetic acid =20:10:1) 7.7(1H, d), 7.6-7.4(3H, m),     7.0-6.8(3H, m),6.75(1H, d), 6.6(1H, d), 5.7(1H, s),4.8-4.4(2H, m),     4.0(2H, t), 3.55(2H, t) 2900, 1640, 1600,1530, 1500, 1480,1450 265     palebrownpowder       1(45)            ##STR110##      0.4(benzene:dioxan:acetic acid =20:10:1) 7.7(1H, d), 7.6-7.4(3H, m),     7.0-6.8(3H, m),6.75(1H, d), 5.7(1H, s), 4.8-4.4(2H, m),4.0(2H, t),     2.0-1.6(6H, m), 1.5-0.9(5H, m) 3300, 2920, 1650,1600, 1510, 1450, 1250     461(M.sup.+)243 palebrownpowder       1(46)            ##STR111##      0.4(benzene:dioxan:acetic acid =20:10:1) 7.75(1H, d), 7.6-7.4(3H, m),     7.0-6.8(3H,m), 6.75(1H, d), 6.6(1H, d), 5.75(1H, s),4.8-4.5(2H, m),     4.05(2H, s), 3.7(2H, s) 2950, 1650, 1600,1540, 1500, 1450,1250 237     palebrownpowder       1(47)            ##STR112##      0.4(benzene:dioxan:acetic acid =20:10:1) 7.7(1H, d), 7.6-7.4(3H, m),     7.0-6.8(3H, m), 6.8-6.7(1H, m), 6.6(1H, d),6.7(1H, m), 4.8-4.4(2H, m),     4.0(2H, t),3.6(2H, t) 2950, 1650, 1600,1540, 1500, 1450,1250 252     whitepowder       1(48)            ##STR113##      0.30(methylenechloride:methanol =5:1) 7.88(2H, d), 7.26(1H, dd),     6.97(2H, d),6.90(1H, t), 6.77(1H, dd), 6.00-5.60(3H, m), 4.80-4.50(4H,     m) 3300, 3300-2300,1640, 1610, 1550,1510, 1460, 1260 421(M.sup.+)301,     219,203 paleyellowpowder       1(49)            ##STR114##      0.38(methylenechloride:methanol =5:1) 7.85(2H, d), 7.29(1H, dd),     6.92(2H, d),6.87(1H, t), 6.73(1H, dd), 5.80-5.68(1H, m), 5.65-5.33(2H,     m), 4.66(1H, dd),4.52(1H, dd) 3420, 3300,3300-2200, 1630,1600, 1540,     1500,1460, 1250, 840,770 435(M.sup.+)409, 217,191 whitepowder   1(50)      ##STR115##      0.25(chloroform:methanol =4:1) 7.45-7.80(3H, m), 7.36(1H, dd), 6.80-7.00     (2H, m), 6.72(1H, dd), 6.60(1H, d),5.70(1H, m), 4.66(1H, dd), 4.51(1H,     dd),4.04(2H, t), 1.85(2H, m), 1.30-1.60(4H, m), 0.95(3H, t)  3350, 2940,     2860,1660, 1610, 1600,1530, 1495, 1455,1265, 1200, 1100, 1060,970, 915,     850, 810 469(M.sup.+)251, 219,181, 153,69 palebrownpowder   1(51)      ##STR116##      0.25(chloroform:methanol =4:1) (CDCl.sub.3)7.80-8.05(3H, m), 7.15-7.45(4     H, m), 6.70-7.15(5H, m), 5.76(1H, m), 5.13(2H, s),4.93(1H, dd), 4.50(1H,     dd), 2.67(2H, t), 1.90(1H, s), 1.64(2H, m), 1.34(4H, m), 0.88(3H, t)     3400, 2940, 2860,1640, 1610, 1540,1500, 1460, 1380,1320, 1255, 1180,     1100,1005, 900, 845, 780 499(M.sup.+)379, 281,219, 181,169, 161,121,     105, 69 whitepowder       1(52)            ##STR117##      0.25(chloroform:methanol =3:1) (CDCl.sub.3 )7.75-8.15(3H, m), 7.10-7.40(     4H, m),6.70-7.10(5H, m), 5.73(1H, m), 5.09(2H,s), 4.87(1H, dd), 4.47(1H,     dd), 2.62(2H, t),1.60(2H, m), 1.35(2H, m), 0.92(3H, t) 3410, 2930,     2860,1635, 1605, 1540,1500, 1455, 1380,1320, 1260, 1180,1100, 900, 840,     780 485(M.sup.+)421, 365,301, 267,219, 147,121, 105 whitepowder   1(53)      ##STR118##      0.50(methylenechloride:methanol =5:1) 7.72(1H, d), 7.55(1H, d),     7.50(2H, d),6.90(1H, t), 6.89(2H, d), 6.73(1H, dd),6.59(1H, d), 5.80-5.68     (1H, m), 5.38-5.68(2H, m), 4.66(1H, dd), 4.54(1H, dd) 3700-2200,     1650,1600, 1540, 1510,1450, 1260, 1180,1100, 1030, 970,830, 780 461(M.sup     .+)436, 315,243, 219217, 181,147 palegreenpowder       1(54)            ##STR119##      0.50(methylenechloride:methanol =5:1) 7.89(2H, d), 7.30(1H, dd),     6.97(2H, d),6.90(1H, t), 6.77(1H, dd), 6.00-5.60(3H, m), 4.72(1H, dd),     4.60-4.50(3H, m) 3400, 3200-2300,1630, 1600, 1540,1500, 1450, 1250     435(M.sup.+)410, 315 whitepowder       1(55)            ##STR120##      0.44(methylenechloride:methanol =5:1) 7.89(2H, dd), 7.31(1H, dd),     6.96(2H, dd),6.90(1H, t), 6.76(1H, dd), 5.98-5.78(1H, m), 5.78-5.72(1H,     m), 5.14-4.94(2H, m), 4.72(1H, dd), 4.55(1H, dd) 3700-2200, 1640,1610,     1550, 1510,1460, 1280, 1180,1100, 1050, 920,840, 780 407(M.sup.+)189,     147,121, 93 palegreypowder       1(56)            ##STR121##      0.30(methylenechloride:methanol =5:1) 7.73(1H, d), 7.50(2H, d),     7.50(1H, d),6.91(2H, d), 6.90(1H, t), 6.75(1H, dd),6.58(1H, d), 5.95-5.60     (3H, m), 4.72-4.56(2H, m), 4.50(2H, d) 3350, 3100-2300,1660, 1600,     1540,1510, 1460, 1260 461(M.sup.+)315, 243,219, 147 white powder   1(57)      ##STR122##      0.51(methylenechloride:methanol =5:1) 7.90(2H, dd), 7.31(1H, dd),     6.98(2H, dd),6.91(1H, t), 6.78(1H, dd), 5.98-5.60(3H, m), 4.74(1H, dd),     4.57(1H, dd),4.54(2H, dd) 3420, 2930, 3700-2200,1640, 1610, 1550,     1510,1460, 1320, 1260, 1180,1100, 1050, 970, 910,840, 780 477(M.sup.+)259     , 219,121, 69 palebrownpowder       1(58)            ##STR123##      0.51(methylenechloride:methanol =3:1) (CDCl.sub.3)7.87(3H, m), 6.89(5H,     m), 5.37(1H, m),4.94(1H, m), 4.51(1H, m), 4.01(2H, t),3.97(2H, t) 3400,     1630, 1600,1530, 500, 1450,1310, 1250, 1170,1090, 1040, 840,770 471(M.sup     .+)435, 253 whitepowder       1(59)            ##STR124##      0.5(methylenechloride:methanol =3:1) (CDCl.sub.3)7.86(3H, m), 6.86(5H,     m), 5.76(1H, m),4.99(1H, m), 4.52(1H, m), 4.01(2H, t),3.53(2H, t) 3400,     1630, 1600,1520, 1490, 1450,1250, 1170, 1100,1000, 840, 770 485(M.sup.+)4     49, 267 whitepowder       1(60)            ##STR125##      0.51(methylenechloride:methanol =3:1) (CDCl.sub.3)7.86(3H, m), 6,89(5H,     m), 5.76(1H, m),4.98(1H, m), 4.52(1H, m), 4.02(2H, t),3.53(2H, t) 3400,     1630, 1600,1540, 1500, 1450,1320, 1260, 1170,1090, 1040, 840,770     499(M.sup.+)463, 281 whitepowder       1(61)            ##STR126##      0.45(chloroform:methanol =3:1) (CDCl.sub.3)7.88(3H, m), 7.40(5H, m),     7.04-6.74(5H, m), 5.76(1H, m), 5.16(2H, s),5.00(1H, m), 4.52(1H, m)     3400, 1620, 1600,1530, 1490, 1450,1320, 1250, 1170,1090, 1000 429(M.sup.+     )309 whitepowder       1(62)            ##STR127##      0.5(chloroform:methanol =3:1) 7.56(4H, m), 7.01-6.70(5H, m), 5.85(1H,     m), 4.60(2H, m), 4.01(2H, t),3.55(2H, t) 3400, 1650, 1590,1530, 1500,     1450,1250, 1170, 1090,960, 820      ##STR128##      palebrownpowder       1(63)            ##STR129##      0.46(chloroformmethanol =3:1) (CD.sub.3      OD)7.72-7.30(10H, m), 7.04-6.66(5H, m),5.80(1H, m), 5.23(2H, s),     4.56(2H, m) 3400, 1640, 1590,1490, 1440, 1240,1160, 1090, 990,810, 730     455(M.sup.+ ) whitepowder       1(64)            ##STR130##      0.30(methylenechloride:methanol =3:1) 7.90(2H, d), 7.30(1H, d),     6.98(2H, d),6.92(1H, t), 6.78(1H, dd), 5.82-5.74(1H, m), 5.56-5.42(1H,     m), 5.14-5.04(1H, m) 3400, 2900, 3200-2300, 1635, 1605,1545, 1505,     1460,1260 475(M.sup.+)355, 340,243, 219 whitepowder       1(65)            ##STR131##      0.58(methylenechloride:methanol =5:1) 7.90(2H, dd), 7.32(1H, dd),     6.97(2H, dd),6.91(1H, t), 6.77(1H, dd), 5.96-5.60(4H, m), 5.10-4.86(2H,     m), 4.72(1H, dd),4.65-4.40(3H, m) 3600-2200, 1640, 1600,1550, 1510,     1460, 1380,1320, 1260, 1180, 1100,1050, 1000, 910, 840,780 447(M.sup.+)33     9, 229,219, 121,109, 93,69 whitepowder               1(66)            ##STR132##      0.30(methylenechloride:methanol =5:1) 7.89(2H, dd), 7.30(1H, dd),     6.98(2H, dd),6.91(1H, t), 6.77(1H, dd), 6.04-5.60(3H, m), 4.73(1H, dd),     4.65-4.46(3H, m) 3700-2100, 1640, 1600,1550, 1510, 1460, 1380,1320,     1260, 1180, 1100,1050, 1000, 970, 900,840, 780 407(M.sup.+)219, 189,149,     121,93, 69 whitepowder       1(67)            ##STR133##      0.33(methylenechloride:methanol =5:1) 7.73(1H, d), 7.48(2H, d),     7.48(2H, d),6.88(2H, d), 6.89(1H, t), 6.74(2H, dd),6.57(1H, d)      ##STR134##      ##STR135##      whitepowder       1(68)            ##STR136##      0.47(methylenechloride: methanol =5:1) 7.89(2H, dd), 7.30(1H, dd),     6.96(2H, dd),6.91(1H, t), 6.77(1H, dd), 5.77(1H, s),4.74(1H, dd),     4.55(1H, dd), 4.02(2H, t) 3700-2200, 2960, 1640,1610, 1540, 1510,     1460,1390, 1320, 1260, 1180,1100, 1040, 900, 840,780, 720 437(M.sup.+)     219, 149,121, 93,69 whitepowder       1(69)            ##STR137##      0.37(chloroform:methanol =4:1) 7.67(1H, d), 7.49(2H, d), 7.28(2H,     d),6.90(1H, t), 6.74(1H, d), 5.72(1H, dd),4.67(1H, dd), 4.46(1H, dd),     2.62(2H, t),1.59(2H, m), 1.28(6H, m), 0.86(3H, t) 3600-2400, 2210,1610,     1590, 1540,1460, 1330, 1260,1090, 1040, 940,820, 770 421(M.sup.+)219,213 y     ellowpowder       1(70)            ##STR138##      0.31(methylenechloride:methanol =5:1) 7.93(1H, d), 7.58(2H, d),     7.58(1H, d),6.90(2H, d), 6.89(1H, t), 6.74(1H, dd),6.54(1H, d) 3300,     3200-2300,1650, 1595, 1540,1505 447(M.sup.+)301, 245 whitepowder   1(71)      ##STR139##      0.37(methylenechloride:methanol =5:1) 7.89(2H, dd), 7.30(1H, dd),     6.97(2H, dd),6.91(1H, t), 6.77(1H, dd), 6.00-5.60(3H, m), 4.73(1H, dd),     4.56(1H, dd),4.52(2H, d) 3700-2200, 1640, 1600,1550, 1510, 1460,     1380,1320, 1260, 1180, 1100,1050, 1000, 970, 910,840, 780, 720 393(M.sup.     +)339, 219,179, 149,121, 93 whitepowder       1(72)            ##STR140##      0.35(methylenechloride:methanol =5:1) 7.69(1H, d), 7.50(1H, d),     7.40(2H, d),6.88(2H, d), 6.86(1H, t), 6.70(1H, dd),6.55(1H, d) 3350,     3200-2300,1650, 1600, 1530,1500, 1450, 1255 433(M.sup.+)287, 215     paleyellowpowder       1(73)            ##STR141##      0.30(methylenechloride:methanol =5:1) 7.73(1H, d), 7.50(1H, d),     7.48(2H, d),6.88(2H, d), 6.89(1H, t), 6.74(1H, dd),6.58(1H, d) 3350,     3200-2300,1650, 1595, 1530,1505, 1450, 1270 433(M.sup.+)215 paleyellowpow     der       1(74)            ##STR142##      0.20(chloroform:methanol =4:1) 7.85(2H, d), 7.10-7.40(6H, m), 6.92(2H,d)     , 6.84(1H, d), 6.73(1H, d), 5.72(1H, m),4.75(1H, dd), 5.40(1H, dd),     4.21(2H, t),3.11(2H, t) 3420, 3240, 3030, 2950,2870, 2740, 1605,     1535,1500, 1460, 1250, 1170,1095, 1040, 1020, 910,840, 765 443(M.sup.+)40     8, 225,201, 131,121, 10584 whitepowder       1(75)            ##STR143##      0.20 (chloroform:methanol =4:1) 7.70(1H, d), 7.40(2H, d), 7.15-7.40(6H,     m), 6.75-6.90(3H, m), 6.68(1H, d),6.50(1H, d), 5.68(1H, m), 4.45-4.80(2H,      m), 4.15(2H, t), 3.08(2H, t) 3400, 3040, 2870,1660, 1605, 1540,1510,     1450, 1260,1200, 1175, 1100,1020, 965, 830, 700. 469(M.sup.+)433,     251,215, 147,105 paleyellowpowder       1(76)            ##STR144##      0.20(chloroform:methanol =4:1) (CDCl.sub.3)8.00(1H, s), 7.86(2H, d),     7.10-7.40(5H, m), 6.70-7.00(5H, m), 5.74(1H, m),4.88(1H, dd), 4.50(1H,     dd), 4.02(2H, m),2.70(2H, m), 1.85(4H, m) 3400, 3030, 2950,1635, 1605,     1540,1505, 1460, 1260,1175, 1095, 840,770, 700 . 471(M.sup.+)253, 121,91 w     hitepowder       1(77)            ##STR145##      0.20 (chloroform:methanol =4:1) 7.70(1H, d), 7.45(2H, d), 71.0-7.55(6H,     m), 6.80-6.95(3H, m), 6.71(1H, d),6.56(1H, d), 5.70(1H, m), 4.45-4.80(2H,      m), 3.97(2H, m), 2.70(2H, m),1.80(4H, m) 3350, 3030, 2950,2870, 1660,     1600,1540, 1510, 1450,1260, 1200, 1175,1105, 970, 830, 780 497(M.sup.+)27     9, 219,147, 91 paleyellowpowder       1(78)            ##STR146##      0.20(chloroform:methanol =4:1) (CDCl.sub.3)7.97(1H, s), 7.89(2H, d),     7.03(2H, d),6.70-7.00(3H, m), 5.75(1H, m), 4.90(1H,dd), 4.73(2H, m),     4.49(1H, dd), 2.22(2H,t), 1.62(1H, m), 1.40(2H, m), 0.87(6H, d) 3400,     2960, 1635,1605, 1540, 1500,1460, 1260, 1230,1175, 1095, 1000,840, 775     447(M.sup.+)279, 229,147, 121,91 whitepowder       1(79)            ##STR147##      0.45(methylenechloride:methanol =5:1) 7.75(1H, d), 7.51(2H, d),     7.51(1H, d),6.92(2H, d), 6.91(1H, t), 6.76(1H, dd),6.60(1H, d), 6.00-5.62     (3H, m), 4.74-4.44(4H, m) 3700-2200, 1660, 1600,1550, 1520, 1490,     1460,1260, 1180, 1100, 1050,970, 920, 830, 780,720 419(M.sup.+)219,     201,147, 105 paleyellowpowder       1(80)            ##STR148##      0.33(methylenechloride:methanol =5:1) 7.72(1H, d), 7.48(2H, d),     7.44(1H, d),6.89(2H, d), 6.88(1H, t), 6.73(1H, dd),6.55(1H, d), 6.00-5.60     (3H, m), 4.70-4.56(2H, m), 4.48(2H, d) 3350, 3200-2300,1650, 1690,     1530,1500, 1440, 1250 503(M.sup.+)357 white powder       1(81)            ##STR149##      0.34(methylenechloride: methanol =5:1) 7.88(2H, d), 7.32(1H, dd),     6.95(2H, d),6.90(1H, t), 6.76(1H, dd), 5.80-5.72(1H, m), 4.70(1H, dd),     4.55(1H, dd),4.01(2H, t) 3400, 3200-2300,1630, 1600, 1540,1500, 1460,     1250 451(M.sup.+)233121 whitepowder       1(82)            ##STR150##      0.30(methylenechloride:methanol =5:1) 7.75(1H, d), 7.50(2H, d),     7.45(1H, d),7.36-7.15(5H, m), 6.91(1H, t), 6.89(2H,d), 6.76(1H, dd),     6.66(1H, d), 5.75(1H,5), 4.63(2H, d), 3.98(2H, t) 3350, 3100-2250,1660,     1600, 1540,1510, 1450, 1260 511(M.sup.+)293251219 whitepowder   1(83)      ##STR151##      0.35(methylenechloridemethanol =5:1) 7.87(2H, d), 7.36-7.11(6H, m),     6.94(2H,d), 6.80(1H, t), 6.76(1H, dd), 5.75(1H,dd), 4.72(1H, dd),     4.55(1H, dd),4.00(2H, t) 3400, 3100-2250,1630, 1600, 1540,1505, 1450,     1300,1260 485(M.sup.+)267 whitepowder       1(84)            ##STR152##      0.45(methylenechloridemethanol =5:1) 7.88(2H, d), 7.32(1H, dd),     6.95(2H, d),6.90(1H, t), 6.76(1H, dd), 5.76(1H, t),4.75-4.50(2H, m),     4.01(2H, t) 3440, 2930, 2850,1640, 1610, 1550,1510, 1460, 1260 477(M.sup.     +)259231 whitepowder       1(85)            ##STR153##      0.32(methylenechloridemethanol =5:1) 7.72(1H, d), 7.48(2H, d), 7.44(1H,     d),6.88(1H, t), 6.87(2H, d), 6.73(1H, dd),6.57(1H, d), 5.71(1H, m),     4.68-4.51(2H, m), 3.97(2H, d) 3430, 2930, 2850,1660, 1600, 1540,1510,     1450, 1260 503(M.sup.+)285 yellowpowder       1(86)            ##STR154##      0.30(methylenechloride:methanol =5:1) 7.72(1H, d), 7.48(2H, d),     6.88(1H, t),6.87(2H, d), 6.73(1H, dd), 6.56(1H, d),0.87(6H, d) 3350,     3200-2300,1655, 1600, 1540,1510, 1450, 1260 477(M.sup.+)259 paleyellowpow     der       1(87)            ##STR155##      0.32(methylenechloride:methanol =5:1) 7.89(2H, d), 7.27(1H, dd),     6.96(2H, d),6.90(1H, t), 6.77(1H, dd), 5.70-5.30(2H, m) 3400, 3200-2300,1     640, 1605, 1545,1500, 1450, 1260 449(M.sup.+)369231 whitepowder   1(88)      ##STR156##      0.32(methylenechloride:methanol =5:1) 7.89(2H, d), 7.44(2H, d),     7.38(1H, dd),6.91(1H, t), 6.77(1H, dd), 4.55(2H, s) 3350, 3200-2300,1630,      1605, 15351450, 1090 437(M.sup.+) 287219 whitepowder       1(89)            ##STR157##      0.45(methylenechloride:methanol =5:1) 7.89(2H, d), 7.36(1H, d),     6.94(2H, d),6.91(1H, t), 6.76(1H, d), 3.68(3H, s) 3325, 3200-2300,1730,     1640, 1610,1460, 1260 467(M.sup.+)391, 322 whitepowder       1(90)            ##STR158##      0.45(methylenechloride:methanol =5:1) 7.82(2H, d), 7.41(1H, dd),     7.32(2H, d),6.91(1H, t), 6.76(1H, d), 2.97(21H, t) 3400, 3200-2300,1645,     1620, 1605,1550, 1460, 1100. 453(M.sup.+)302, 235 whitepowder   1(91)      ##STR159##      0.38(methylenechloride:methanol =5:1) 7.76(1H, d), 7.52(2H, d),     7.34(2H, d),6.88(1H, t), 6.73(1H, dd), 6.70(1H, d),4.50(2H, s), 3.50(2H,     t), 0.90(6H, d) 3370, 3200-2300,1660, 1610, 1545,1460, 1260, 1100     449(M.sup.+)245, 231,219 whitepowder       1(92)            ##STR160##      0.34(methylenechloride:methanol =5:1) 7.72(1H, d), 6.49(2H, d),     7.17(1H, dd),6.00-6.80(6H, m), 6.74(1H, dd), 6.57(1H, d), 4.21(2H, t),     3.32(2H, t) 3350, 3200-2300,1660, 1610, 1540,1510, 1460, 1260,1180, 830     475(M.sup.+)365, 257,219 whitepowder       1(93)            ##STR161##      0.33(methylenechloride:methanol =5:1) 7.50(1H, s), 7.58(1H, d),     7.37(2H, d),6.93(2H, d), 6.84(1H, t), 6.84-6.74(2H, m), 5.80(1H, m),     2.38(3H, d),0.92(6H, d) 3400, 3200-2300,1635, 1600, 1505,1260 463(M.sup.+     ) 245, 161 whitepowder       1(94)            ##STR162##      0.33(methylenechloride:methanol =5:1) 7.87(2H, d), 7.41(1H, dd),     6.94(2H, dd),6.90(1H, t), 6.74(1H, dd), 4.04(2H, t) 3350, 3200-2300,1630,      1600, 1540,1500, 1450, 1245 449(M.sup.+)406, 393,355, 231 whitepowder     1(95)      ##STR163##      0.34(methylenechloride:methanol =5:1) 7.88(2H, dd), 7.35(1H, dd),     7.17(1H, dd),7.01-6.84(5H, m), 6.75(1H, dd),5.80-5.72(1H, m), 4.68(1H,     dd), 4.55(1H, dd) 3700-2200, 1640,1610, 1540, 1500,1470, 1260, 1180,1100,      900, 840,700 449(M.sup.+)355, 231,219, 149,121, 111 whitepowder   1(96)      ##STR164##      0.35(methylenechloride:methanol =5:1) 7.88(2H, dd), 7.34(1H, dd),     6.94(2H, dd),6.90(1H, t), 6.76(1H, dd), 5.80-5.72(1H, m), 4.69(1H, dd),     4.55(1H, dd) 3600-2200, 1740,1640, 1600, 1550,1510, 1460, 1260,1180,     1100, 1040,850, 780 481(M.sup.+)263, 219,149, 121 whitepowder   1(97)      ##STR165##      0.41(methylenechloride:methanol =5:1) 7.73(1H, d), 7.47(2H, d),     7.38(1H, d),6.87(1H, t), 6.86(2H, d), 6.73(1H, dd),4.06(2H, t) 3600-2200,      1740,1660, 1600, 1540,1520, 1460, 1260,1180, 1100, 1040,970, 830     507(M.sup.+)464, 289,219, 121 paleyellowpowder       1(98)            ##STR166##      0.30(methylene chloride:methanol =5:1) 7.72(2H, d), 7.46(1H, d),     6.84(2H, d),6.87(1H, t), 6.72(1H, dd), 6.55(1H, d),5.80-5.66(1H, m),     4.80-4.50(2H, m) 3400, 3200-2300,1655, 1600, 1530,1510, 1450, 1260     475(M.sup.+)381, 223,257, 147 paleyellowpowder       1(99)            ##STR167##      0.41(methylenechloride:methanol =5:1) 7.89(2H, d), 7.34(1H, dd),     6.96(2H, d),6.91(1H, t), 6.77(1H, dd), 4.02(2H, t) 3410, 3150-2250,1640,     1610, 1540,1510, 1460, 1260 449(M.sup.+)231 whitepowder   1(100)      ##STR168##      0.33(methylenechloride:methanol =5:1) 7.79(2H, dd), 7.37(1H, dd),     7.35-7.15(5H, m), 6.95(2H, dd), 6.92(1H, t),6.78(1H, dd), 5.82-5.73(1H,     m) 3600-2200, 1630,1600, 1550, 1520,1470, 1330, 1270,1190, 1100,     1040,850, 780, 710  457(M.sup.+)239, 219,121 whitepowder   1(101)      ##STR169##      0.33(methylenechloridemethanol =5:1) 7.96(2H, d), 7.52(1H, dd),     7.22(2H, d),7.25-7.14(1H, m), 6.93(1H, t), 6.78(1H, dd), 6.03(1H, d),     5.90-5.70(1H,m), 4.80-4.50(2H, m) 3400, 3200-2300,1730, 1630, 1595,1530,     1200 463(M.sup.+)339, 245,121, 125 whitepowder       1(102)            ##STR170##      0.48(methylenechloridemethanol =5:1) 7.89(2H, dd), 7.38(1H, dd),     6.96(2H, dd),6.91(1H, t), 6.76(1H, dd), 5.81-5.73(1H, m), 4.69(1H, dd),     4.56(1H, dd) 3600-2100, 29501640, 1600, 1550,1510, 1460, 1320,1260,     1180, 1100,1050, 850 479(M.sup.+)261, 219,121, 93 whitepowder   1(103)      ##STR171##      0.27(methylenechloridemethanol =5:1) 7.72(1H, d), 7.50(2H, d), 7.30-7.14     (5H,m), 6.90(1H, t), 6.88(2H, d), 6.74(1H,dd), 6.59(1H, d), 5.78-5.68(1H,      m),4.68(1H, dd), 4.53(1H, dd) 3700-2100, 1660,1600, 1540, 1510,1450,     1270, 1180,1100, 1030, 980,830, 700 483(M.sup.+) 265, 219,147, 119,91     paleyellowpowder       1(104)            ##STR172##      0.25(methylenechloridemethanol =4:1) (CDCl.sub.3)8.00(1H, s), 7.87(2H,     d), 7.33(2H, d),7.20(2H, d), 7.02(2H, d), 6.98(1H, d),6.86(1H, t),     6.75(1H, d), 5.74(1H, m),5.10(2H, s), 4.86(1H, dd), 4.48(1H, dd) 3300,     2960, 2870,1620, 1605, 1500,1465, 1250, 1175,1100 471(M.sup.+), 428415,     377, 351339, 253, 223219, 205, 149133, 121, 91 whitepowder    1(105)      ##STR173##      0.35(methylenechloridemethanol =5:1) 7.91(1H, d), 7.45-7.20(6H, m),     7.02(2H,d), 6.91(1H, t), 6.76(1H, dd), 6.74(1H,d), 6.39(1H, dt) 3400,     3200-2300,1630, 1600, 1540,1495, 1450, 1250 455(M.sup.+)335, 281     paleyellowpowder       1(106)            ##STR174##      0.32(methylenechloride:methanol =5:1) 8.06(4H, s), 7.72(1H, dd),     6.97(1H, t),6.80(1H, dd), 5.76(1H, m), 4.65(2H, m),3.00(2H, t) 3300,     3200-2300,1680, 1630, 1530,1460, 1275 449(M.sup.+)299, 231 whitepowder     1(107)      ##STR175##      0.20(chloroform:methanol =4:1) (CDCl.sub.3)8.03(1H, s), 7.35-7.60(5H,     m), 7.15(1H,s), 6.96(2H, d), 6.60-6.70(5H, m), 5.80(1H, m), 4.97(1H,     dd), 4.49(1H, dd),3.89(2H, t) 3390, 2950, 1655,1605, 1540, 1510,1450,     1260, 1175 525(M.sup.+)307, 279,195, 165,121 yellowpowder   1(108)      ##STR176##      0.25(methylenechloride:methanol =5:1) 7.88(2H, d), 7.33(1H, dd),     7.34-7.10(5H, m), 6.94(2H, d), 6.90(1H, t),6.75(1H, dd), 4.12(2H, t)     3460-2210, 1640,1610, 1540, 1510,1460, 1260 489(M.sup.+)271 whitepowder      1(109)      ##STR177##      0.20(chloroform:methanol =5:1) (CDCl.sub.3)8.05(1H, s), 7.86(2H, d),     7.13(1H, dd),6.65-7.05(7H, m), 5.74(1H, m), 4.85(1H,dd), 4.49(1H, dd),     4.02(2H, m), 2.93(2H, m), 1.90(4H, m) 2950, 1630, 1605,1540, 1500,     1455,1255, 1175, 1090,840, 770, 690 477(M.sup.+)307, 259,139, 121,97     y     paleellowpowder       1(110)            ##STR178##      0.20(chloroform:methanol =4:1) (CDCl.sub.3)7.96(1H, s), 7.85(2H, d),     7.10-7.35(3H,m), 6.70-7.00(7H, m), 5.72(1H, m), 4.86(1H, dd), 4.47(1H,     dd), 4.20(2H, t),4.14(2H, t), 2.28(2H, m) 3400, 2940, 2870,2730, 1630,     1600,1540, 1490, 1460,1250, 1175, 1095,1050, 760, 690 473(M.sup.+)255,     135,121, 107 whitepowder       1(111)            ##STR179##      0.30(methylenechloride:methanol =5:1) 7.88(2H, d), 6.97(3H, d),     6.88(1H, t),6.77(1H, dd), 6.35(1H, dd), 6.07(1H,dd), 5.86-5.65(3H, m),     4.85(1H, dd),4.60(2H, d), 4.52(1H, dd) 3400, 2960, 2930,2860, 1600,      1     1530,500, 1450, 1380, 1250 447(M.sup.+)327, 229,219 white powder     1(112)      ##STR180##      0.20(chloroform:methanol =4:1) (CDCl.sub.3)7.94(1H, s), 7.87(2H, d),     6.70-7.00(5H,m), 5.74(1H, m), 4.90(1H, dd), 4.48(1H,dd), 4.02(2H, t),     3.30(2H, t), 1.10-2.20(7H, m) 3410, 2940, 2870,2730, 2090, 1635,1600,     1540, 1505,1460, 1260, 1180,1095, 845, 770 450(M.sup.+)232, 121,84     whitepowder       1(113)            ##STR181##      0.43(methylenechloride:methanol =5:1) 7.89(2H, d), 7.39(1H, dd),     6.96(2H, d),6.91(1H, t), 6.76(1H, dd), 4.04(2H, t) 3650-3150, 2940,1630,     1605, 1545,1505, 1460, 1260 (M.sup.+)487269 whitepowder   1(114)      ##STR182##      0.22(methylenechloride:methanol =5:1) 7.87(2H, d), 7.42(1H, dd),     7.36-7.20(5H, m), 6.90(2H, d), 6.90(1H, t),6.76(1H, dd), 4.19(2H, t),     3.30(2H, t) 3400, 3100-2200,1600, 1540, 1500,1460, 1250 475(M.sup.+)257     whitepowder       1(115)            ##STR183##      0.30(methylenechloride:methanol =5:1) 7.92(2H, d), 7.38(1H, d),     7.30(2H, t),7.10-6.87(6H, m), 6.77(1H, dd), 5.77(1H, dd), 4.70(1H, dd),     4.56(1H, dd),4.37(4H, s) 3600-2500, 1730,1630, 1605, 1570,1530, 1485,     1460,1380, 1285, 1245,1200 459(M.sup.+)241, 218 yellowpowder   1(116)      ##STR184##      0.31(methylenechloride:methanol =5:1) 7.89(2H, d), 7.41(1H, dd),     6.95(2H, d),6.91(1H, t), 6.75(1H, dd), 4.50(2H, t),4.07(2H, t) 3350,     2900, 1630,1605, 1540, 1505,1460, 1260 decom-posed whitepowder   1(117)      ##STR185##      0.30(methylenechloride:methanol =5:1) 7.92(2H, d), 7.46(1H, dd),     7.00(2H, d),6.92(1H, t), 6.76(1H, dd), 5.76(1H, dd),4.64(1H, dd),     4.56(1H, dd), 4.21(2H, t) 3650-3150, 3020-2250,2100, 1635, 1605,1540,     1510, 1480,1460, 1340, 1320,1310, 1280, 1260 408(M.sup.+)339, 190 white     powder       1(118)            ##STR186##      0.30(methylenechloride:methanol =5:1) 7.90(2H, d), 7.34(1H, dd),     6.95(2H, d),6.92(1H, t), 6.77(1H, dd), 5.77(1H, dd),4.70(1H, dd),     4.56(1H, dd), 4.06(2H, t),3.39(2H, t) 3620-3150, 2920,2100, 1605,     1540,1505, 1460, 1260 436(M.sup.+)218 whitepowder       1(119)            ##STR187##      0.30(methylenechloride:methanol =5:1) 7.86(2H, d), 7.80(3H, m),7.72(1H,     s), 7.58(1H, dd),7.44(3H, m), 6.95(2H, d),6.90(1H, t), 6.73(1H, dd),5.68(     1H, t), 4.55(2H, d) 3700-2300, 1650,1610, 1520, 1510,1455, 1260 493(M.sup     .+),450, 437,399, 275 whitepowder       1(120)            ##STR188##      0.30(methylenechloride:methanol =5:1)   491(M.sup.+)273, 115111     whitepowder       1(121)            ##STR189##      0.30(methylenechloride:methanol =5:1)   505, 411,287, 253,121 whitepowde     r

EXAMPLE 1(201)-1 (260)

By the same procedure as example 1, using with a correspondingcarboxylic acid and a corresponding8-amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran hydrochloride which havecorresponding substituent R³ following compounds having the followingphysical data, shown in table [IX] were given. ##STR190##

    TABLE IX        Substituent R, R.sup.3 Rf value in TLC     Example in the general     (developing No. formula (In) solvent) NMR (δppm) IR (νcm.sup.-1)      Mass Appearance              1 (201)      0.26(chloroform:methanol =3:1) 8.81(1H, dd), 7.95(1H, dd), L7.76(1H,     d)7.57(2H, d), 7.52(1H, t), 7.28(1H, s),7.25(2H, d), 7.10(1H, d),     2.56(2H, t),1.66(2H, m), 1.20-1.50(4H, m),0.91(8H, t) 3310, 3060, 2830,     2850,1620-1650, 1585, 1520,1420, 1350, 1280, 1205,1180, 1085, 10005, 970     ,880, 810, 750 429(M .sup.30)401, 391, 385,375, 296, 229,201, 181, 115     palebrownpowder       1 (202)            ##STR191##      0.16(chloroform:methanol =4:1) 8.72(1H, d), 7.76(1H, d), 7.72(1H,     m),7.56(2H, d), 7.24(2H, d), 7.24(1H, s),7.10(1H, d), 2.65(2H, t),     2.52(8H, n),1.65(2H, m), 1.20-1.45(4H, m),0.90(8H, t) 3400, 2980, 2860,     1650,1625, 1600, 1585, 1470,1420, 1370, 1380, 1265,1215, 1180, 1080,     8     980,95, 860 448(M.sup.+)415, 400,248, 201,181 yellowpowder   1 (203)      ##STR192##      0.20(chloroform:methanol =4:1) 8.80(1H, dd), 7.80(1H, d), 7.50-7.658H,     m), 7.26(1H, s), 7.24(2H, d), 7.14(1H, d), 2.65(2H, t), 1.65(2H,     m),1.20-1.45(4H, m), 0.90(8H, t) 3400, 2980, 2850, 1650,1520, 1500,     1520, 1470,1420, 1375, 1325, 1175 419, 404,296, 247,201, 161,181, 115     yellowbrownpowder       1 (204)            ##STR193##      0.15(chloroform: methanol =4:1) 8.80(1H, dd), 7.90(1H, dd), 7.76(1HM,     d),7.55-7.70(2H, m), 7.50(1H, t),7.35-7.50(8H, m), 7.27(1H, s),7.12(1H,     d) 8400, 8020, 1695, 1685,1610, 1585, 1520, 1420,1355, 1280, 1185,     1160,880, 760, 550 359(M.sup.+)331, 816,296, 268229, 201,181, 108     yellowpowder       1 (205)            ##STR194##      0.46(methylenechloride:methanol =4:1) 8.74(1H, dd), 7.99(1H, dd),     7.97(2H, d),7.64(1H, t), 7.88(2H, d), 7.26(1H, s),2.78(2H, t), 0.92(8H,     t) 3500-2800, 1670, 1620,1590, 1535, 1485 408(M.sup.+),349, 175 whitepowd     er       1 (206)            ##STR195##      0.46(chloroform:methanol =3:1) 8.66(1H, dd), 8.02(2H, d), 7.98(1H,dd),     7.63(1H, t), 7.27(1H, s), 7.05(2H, d), 4.08(2H, t), 1.90- 1.76(2H,     m),1.64-1.44(2H, m), 1.02(3H, t) 3600-2300, 1645, 1600,1585, 1580, 1505,     1425,1385, 1290, 1255, 1180,1070, 1030, 970, 890,840, 810, 765 405(M.sup.     +)225, 1 77 paleyellowpowder       1 (207)            ##STR196##      0.46(chloroform:methanol =3:1) 8.60(1H, dd), 8.02(2H, d), 7.98(1H,dd),     7.54(1H, t), 7.27(1H, s), 7.05(2H, d), 4.08(2H, t), 1.94-1.78(2H,     m),1.60-1.25(4H, m), 0.96(3H, t) 3600-2300, 1645, 1600,1585, 1530, 1505,     1425,1385, 1290, 1255, 1180,1070, 1030, 970, 890,840, 810, 765 419(M.sup.     +)379, 2 05 paleyellowpowder       1 (208)            ##STR197##      0.48(chloroform:methanol =3:1) 8.45(1H, dd), 8.02(2H, d), 7.98(1H,dd),     7.53(1H, t), 7.22(1H, s), 7.05(2H, d), 4.07(2H, t), 1.90-1.75(2H,     m),1.60-1.30(6H, m), 1.00-0.90(3H, t) 3600-2300, 1645, 1600,1585, 1530,     1505, 1425,1385, 1290, 1255, 1180,1070, 1030, 970, 890,840, 810, 765     4.33(M.sup.+)379, 205 whitepowder       1 (209)            ##STR198##      0.48(chloroform:methanol =3:1) 8.48(1H, dd), 8.02(2H, d), 7.98(1H,dd),     7.54(1H, t), 7.25(1H, s), 7.04(2H, d), 4.07(2H, t), 1.90-1.75(2H,     m),1.60-1.25(8H, m), 1.00-0.75(3H, t) 3600-2300, 1645, 1600,1585, 1530,     1505, 1424,1385, 1290, 1255, 1180,1070, 1030, 970, 890,840, 810, 765     447(M.sup.30 )394, 219 paleyellowpowder       1 (210)            ##STR199##      0.48(chloroform:methanol =3:1) 8.70(1H, dd), 8.01(2H, d), 7.97(1H,dd),     7.52(1H, t), 7.26(1H, s), 7.03(2H, d), 4.06(2H, t), 1.90-1.76(2H,     m),1.60-1.20(12H, m), 0.96-0.84(3H, t) 3600-2300, 1645, 1600,1585, 1530,     1505, 1425,1385, 1290, 1255, 1180,1070, 1030, 970, 890,840, 810, 765     475(M.sup.+)421, 247 paleyellowpowder       1 (211)            ##STR200##      0.48(chloroform:methanol =5:1) 8.48(1H, dd), 8.02(2H, d), 7.98(1H,     d),7.53(1H, t), 7.27(1H, n), 7.04(2H, d),4.06(2H, t), 1.90-1.75(2H,     m),1.60-1.20(10H, m), 1.00-0.75(3H, t) 3600-2300, 1645, 1600,1585, 1530,     1505, 1425,1385, 1290, 1255, 1180,1070, 1030, 970, 890,840, 810, 765     461(M.sup.+)407, 233 paleyellowpowder       1 (212)            ##STR201##      0.30(methylenechloride:methanol = 8.74(1H, dd), 8.01(2H, d), 7.96(1H,dd)     , 7.52(1H, t), 7.24(1H, s), 7.052H, d), 6.00-5.64(3H, m), 5.10-4.90(2H,     m), 4.58(2H, brd) 3275, 3075, 3500-2300,1650, 1630, 1600, 1570,15101495,     1420, 1250 457(M.sup.+)337, 229121 palebrownpowder       1 (213)            ##STR202##      0.30(methylenechloride:methanol =4:1) 8.66(1H, dd), 8.02(2H, d),     7.96(1H,dd), 7.53(1H, t), 7.26(1H, s), 7.06(2H, d), 5.60-5.44(1H, m),     5.20-5.00(1H, m) 3275, 3050, 3500-2300,1640, 1590, 1570, 1510,1490,     1415, 1240 485(M.sup.+)365, 350231 palebrownpowder       1 (214)            ##STR203##      0.44(chloroform:methanol =4:1) 8.91(1H, dd), 7.94(1H, dd), 7.76(1H,d),     7.58(2H, d), 7.50(1H, t), 7.24(1H,s), 6.99(1H, d), 6.94(2H, d), 4.01(2H,t     ), 1.90- 1.74(2H, m), 1.60-1.30(6H, m),0.92(3H, t) 3600-2300, 1640,      1     1600,535, 1430, 1390, 1355,1190, 1170, 1110, 825,755 paleyellowpowder     1 (215)      ##STR204##      0.44(chloroform:methanol =4:1) 8.82(1H, dd), 7.94(1H, dd), 7.74(1H,d),     7.61(2H, d), 7.52(1H, t), 7.28(1H,s), 7.04(1H, d), 6.96(2H, d), 4.04(2H,t     ), 1.90-1.76(2H, m), 1.60-1.26(8H, m),0.92(3H, t) 3600-2300, 1640,     1600,1535, 1430, 1390, 1355,1335, 1260, 1190, 1170,1110, 1070, 1040,     1010,975, 825, 755 473(M.sup.+)245 paleyellowpowder       1 (216)            ##STR205##      0.42(chloroform:methanol =4:1) 8.84(1H, dd), 7.95(1H, dd), 7.75(1H,d),     7.60(2H, d), 7.52(1H, t), 7.29(1H, s), 7.04(1H, d), 6.96(2H, d),     4.02(2H, t), 1.90-1.76(2H, m), 1.72- 1.56(1H, m), 1.45-1.24(4H, m),     0.96(6H, d) 3600-2300, 1640, 1600,1535, 1430, 1360, 1260,1170, 1040,     1010, 825,755 459(M.sup.+)261, 231 paleyellowpowder       1 (217)            ##STR206##      0.43(chloroform:methanol =4:1) 8.88(1H, dd), 7.94(1H, dd), 7.75(1H,d),     7.49(2H, d), 7.50(1H, t), 7.26(1H,s), 7.02(1H, d), 6.93(2H, d), 4.04(2H,t     ), 3.59(2H, t), 1.96-1.89(4H, m),1.86-1.60(2H, m) 3600-2300, 1645,     1600,1530, 1430, 1390, 1260,1170, 1110, 1070, 1040,1010, 975, 8 25, 755     443425, 251 yellowpowder       1 (218)            ##STR207##      0.43(chloroform:methanol =4:1) 8.86(1H, dd), 7.94(1H, dd), 7.74(1H,d),     7.59(2H, d), 7.51(1H, t), 7.26(1H,s), 7.03(1H, d), 6.96(2H, d), 4.04(2H,t     ), 3.58(2H, t), 1.94- 1.86(4H, m),1.60-1.50(4H, m) 36900-2300, 1645,     1600,1530, 1430, 1370, 1360,1260, 1170, 1110, 1070,1040, 1010, 975,     825,755 493(M.sup.+)457, 439265 yellowpowder       1 (219)            ##STR208##      0.43(chloroform:methanol =4:1) 8.86(1H, dd), 7.96(1H, dd), 7.78(1H,d),     7.56(2H, d), 7.52(1H, t), 7.28(1H,s), 7.25(2H, d), 7.14(1H, d), 2.68(2H,t     ), 1.72-1.56(2H, m), 1.48-1.26(2H, m),0.96(3H, t) 3600-2300, 1640,     1585,1520, 1430, 1380, 1350,1280, 1180, 1110, 1070,1040, 1010, 975,     890,820, 755 415( M.sup.+)231, 187 palebrownpowder       1 (220)            ##STR209##      0.43(chloroform:methanol =4:1) 8.86(1H, dd), 7.95(1H, dd), 7.78(1H,d),     7.57(2H, d), 7.52(1H, t), 7.28(1H,s), 7.24(2H, d), 7.11(1H, d), 2.66(2H,t     ), 1.74-1.56(2H, m), 1.44-1.24(6H, m),0.89(3H, t) 3600-2300, 1640,     1590,1520, 1425, 1385, 1350,1280, 1080, 1110, 1065,1040, 1005, 975,     890,820, 755 433( M.sup.+)215 whitepowder       1 (221)            ##STR210##      0.43(chloroform:methanol =4:1) 8.84(1H, dd), 7.95(1H, dd), 7.76(1H,d),     7.58(2H, d), 7.52(1H, t), 7.28(1H,s), 7.20(2H, dd), 7.14(1H, d),     2.65(2H, t), 1.74-1.58(2H, m), 1.40-1.20(8H, m), 0.88(3H, t) 3500-2300,     1640, 1585,1520, 1430, 1350, 1180,1110, 1040, 1005, 975,885 457(M.sup.+)2     29 whitepowder       1 (222)            ##STR211##      0.30(methylenechloride:methanol =4:1) 8.72(1H, dd), 8.00(2H, d),     7.95(1H,dd), 7.50(1H, t), 7.23(1H, s), 7.04(2H, d), 6.00-5.60(2H, m),     4.56(2H, brd) 3300, 3500-2300, 1640,1595, 1570, 1515, 1490,1415, 1240     473(M.sup.+)353, 245121 brownpowder       1 (223)            ##STR212##      0.30(methylenechloride:methanol =4:1) 8.74(1H, dd), 8.02(2H, d),     7.96(1H,dd), 7.50(1H, t), 7.23(1H, s), 7.10(2H, d), 4.77(2H, t) 3375,     3050, 3500-2300, 1640, 1590, 1570, 1510,1490, 1415, 1240 457(M.sup.+)429,      229175, 121 palebrownpowder       1 (224)            ##STR213##      0.41(methylenechloride:methanol =4:1) 8.65(1H, dd), 8.01(2H, d),     7.96(1H,dd), 7.52(1H, t), 7.25(1H, s), 7.04(2H, d), 4.16-4.06(2H, m),     3.70-3.60(2H, m), 2.10-1.96(4H, m) 3600-2300, 1650, 16001585, 1530,     1505, 1430,1380, 1295, 1255, 1180,1115J, 1070, 1035, 890,845, 815, 765,     750 211 whitepowder       1 (225)            ##STR214##      0.41(methylenechloride:methanol =4:1) 8.62(1H, dd), 8.02(2H, d),7.98(1H,d     d), 7.53(1H, t), 7.26(1H, s), 7.05(2H, d), 4.10(2H, t), 3.60(2H,     t),2.00-1.80(4H, m), 1.80-1.60(2H, m) 3600-2300, 1650, 1600,1585, 1530,     1505, 1430,1380, 1295, 1255, 1180,1115, 1070, 1035, 895,84 5, 815, 765,     760 453(M.sup.+)417, 225 whitepowder       1 (226)            ##STR215##      0.44(methylenechloride:methanol =4:1) 8.64(1H, dd), 8.0292H, d),     7.98(1H,dd), 7.53(1H, t), 7.26(1H, s), 7.04(2H, d), 4.08(2H, t),     3.58(2H, t),1.96-1.78(4H, m), 1.62-1.50(4H, m) 3600, 2300, 1650,     1600,1585, 1530, 1505, 1430,1380, 1295, 1255, 1180,1115, 1070, 1035,     8     890,45 , 815, 765, 750 467(M.sup.+)431, 239 whitepowder   1 (227)      ##STR216##      0.30(methylenechloride:methanol =4:1) 8.73(1H, dd), 8.01(2H, d),     7.96(1H,dd), 7.52(1H, t), 7.24(1H, s), 7.05(2H, d), 6.00-5.60(2H, m),     4.58(2H, d) 3500-2300, 1640, 1620,1600, 1580, 1520, 1500,1420, 1245     459(M.sup.+)339, 231 palebrownpowder       1 (228)            ##STR217##      0.38(chloroform:methanol =4:1) 8.58(1H, dd), 8.01(2H, d), 7.98(1H,dd),     7.53(1H, t), 7.32-7.16(5H, m),7.26(1H, s), 7.03(2H, d), 4.06(2H,t),     2.84(2H, t), 2.14-2.06(2H, m) 3600-2300, 1645, 1600,1580, 1525, 1505,     1425,1380, 1290, 1255, 1180,1060, 1030, 885, 835,810, 760, 740 467(M.sup.     +)413, 23 9 whitepowder       1 (229)            ##STR218##      0.37(chloroform:methanol =4:1) 8.64(1H, dd), 8.04(2H, d), 7.98(1H,dd),     7.54(1H, t), 7.48-7.26(5H, m),7.27(1H, s), 7.12(2H, d), 6.80(1H,     d),6.44(1H, d), 4.83(2H, dd) 3600-2300, 1645, 1600,1580, 1520, 1500,     1425,1375, 1290, 1250, 1175,970, 885, 840, 810,765, 745  465(M.sup.+)345,      237 palebrownpowder       1 (230)            ##STR219##      0.38(chloroform:methanol =4:1) 8.57(1H, dd), 8.02(2H, d), 7.98(1H,dd),     7.54(1H, t), 7.30-7.15(5H, m),7.26(1H, s), 7.04(2H, d), 4.14-4.04(2H,     m), 2.76-2.68(2H, m), 1.90-1.80(4H, m) 3600-2300, 1645, 1600,1580, 1525,     1505, 1425,1380, 1290, 1255, 1180,1060, 1030, 885, 835,810, 760, 740     480(M .sup.+)423, 253 palebrownpowder       1 (231)            ##STR220##      0.31(chloroform:methanol =4:1) 8.74(1H, dd), 8.01(2H, d), 7.96(1H,dd),     7.52(1H, T), 7.24(1H, s), 7.03(2H, d), 5.95-5.72(1H, m), 5.10-4.90(2H,     m), 4.06(2H, t) 3100-2300, 1640, 1610,1595, 1575, 1515, 1495,1420, 1245     459(M.sup.+)231, 121 palebrownpowder       1 (232)            ##STR221##      0.43(chloroform:methanol =4:1) 8.60(1H, dd), 8.00(1H, dd), 7.97(2H,d),     7.54(1H, t), 7.38(2H, d), 7.28(1H, s), 2.73(2H, t), 1.80-1.60(2H,     m),1.42-1.22 (8H, m), 0.89(3H, t) 3600-2300, 1645, 1620,1585, 1520,     1425, 1375,1290, 1065, 1030, 1015,890, 810, 765, 750 417(M.sup.+ )363,     189 whitepowder       1 (233)            ##STR222##      0.43(chloroform:methanol =4:1) 8.56(1H, dd), 8.00(1H, dd), 7.97(2H,d),     7.54(1H, t), 7.37(2H, d), 7.20(1H, s), 2.13(2H, t), 1.78-1.60(2H,     m),1.44-1.26(6H, m), 0.90(3H, t) 3600-2300, 1645, 1620,1585, 1520, 1425,     1375,1290, 1065, 1030, 1015,890, 765, 750 431(M.sup.+)377, 203 palebrownp     owder       1 (234)            ##STR223##      0.43(chloroform:methanol =4:1) 8.68(1H, dd), 7.99(1H, dd), 7.96(2H,d),     7.54(1H, t), 7.37(2H, d), 7.27(1H, s), 2.72(2H, t), 1.76-1.60(2H,     m),1.42-1.32(10H, m), 0.88(3H, t) 3600-2300, 1645, 1620,1585, 1525,     1425, 1375,1290, 1065, 1030, 1015,890, 765, 750 445(M.sup.+)391, 217     y     paleellowpowder       1 (235)            ##STR224##      0.43(chloroform:methanol =4:1) 8.65(1H, dd), 8.00(1H, dd), 7.96(2H,d),     7.54(1H, t), 7.38(2H, d), 7.27(1H, s), 2.73(2H, t), 1.76-1.60(2H,     m),1.44-1.24(12H, m), 0.88(3H, t) 3600-2300, 1645, 1620,1585, 1525,     1425, 1375,1290, 1065, 1030, 1015,890, 810, 765, 750 459(M.sup.+)405,     231 paleyellowpowder       1 (236)            ##STR225##      0.29(methylenechloride:methanol =4:1) 8.37(1H, dd), 8.01(2H, d),     7.96(1H,dd), 7.51(1H, t), 7.23(1H, s), 7.13(1H, dd), 7.02(2H, d),     6.92(1H, dd),6.83(1H, brs) 3600-2300, 1640, 1610,1595, 1570, 1510,     1490,1415, 1250 487(M.sup.+)433, 259 palebrownpowder       1 (237)            ##STR226##      0.30(methylenechloride:methanol =4:1) 8.64(1H, dd), 7.92(2H, d),     7.88(1H,dd), 7.18(1H, s), 6.98(2H, d), 7.44(1H, t), 6.00-5.60(2H, m),     4.55 (2H,brd) 3600-2300, 1640, 1610,1590, 1570, 1510, 1490,1420, 1245     445(M.sup.+)325, 231217, 189121 whitepowder       1 (238)            ##STR227##      0.30(methylenechloride:methanol =4:1) 8.70(1H, dd), 8.00(2H, d),     7.95(1H,dd), 7.50(1H, t), 7.24(1H, s), 7.04(2H, d), 6.00-5.60(2H, m),     4.57(2H, d) 3600-2300, 1645, 1620,1595, 1575, 1520, 1495,1420, 1240     431(M.sup.+)311, 203121 paleyellowpowder       1 (239)            ##STR228##      0.45(chloroform:methanol =4:1)  8.53(1H, dd), 8.00(2H, d), 7.57(1H,dd),     7.24(1H, s), 7.05(2H, d), 5.98-5.64(3H, m), 5.06-4.90(2H, m), 4.60(2H,     d), 2.20-2.00(4H, m), 1.60-1.44(2H, m) 3600-2300, 1650, 1600,1510, 1480,     1435, 1390,1260, 1180, 900, 865 475(M.sup.+)355, 244 yellowpowder   1     (240)      ##STR229##      0.45(chloroform) 8.40(1H, dd), 8.00(2H, d), 7.58(1H,dd), 7.24(1H, s),     7.04(2H, d), 4.07(2H, t), 1.90-1.85(2H, m), 1.60-1.25(8H, m), 0.90(3H, t 3     600-2300, 1655, 1600,1510, 1475, 1430, 1380,1260, 1180, 1035, 1015,895,     870 465(M.sup.+)229 yellowpowder       1 (241)            ##STR230##      0.51(chloroform:methanol =4:1) 8.52(1H, d), 7.96(2H, d), 7.70(1H,     d),7.21(5H, m), 7.16(1H, s), 6.97(2H, d),4.04(2H, t), 2.69(2H, t),     2.48(3H, s),1.84(4H, m) 3600-2300, 1645, 1600,1530, 1505, 1250, 1180,1030     , 890, 860, 840,760 441, 253 palebrownpowder       1 (242)            ##STR231##      0.32(chloroform:methanol =3:1) 8.58(1H, d), 8.00(2H, d), 7.73(1H,     d),7.20(1H, s), 7.03(2H, d), 5.60-6.00(2H, m), 4.56(2H, d), 2.52(3H,     s),2.10(2H, m) 2930, 2860, 1650, 1605,160 0, 1535, 1510, 1460,1260,     1180, 1040, 900,770 473(M.sup.+)354, 231121, 11091 yellowpowder   1     (243)      ##STR232##      0.32(chloroform:methanol =3:1) 8.56(1H, d), 7.98(2H, d), 7.71(1H,     d)7.17(1H, s), 7.12(1H, d), 6.99(2H, d),6.91(1H, dd), 6.80(1H, d),     4.06(2H, m),2.92(2H, m), 2.50(3H, s), 1.88(4H, m) 2930, 1650, 1605,      1     1595,535, 1510, 1450, 1260,1180, 1035 510(M.sup.+)477, 259139, 12197     yellowbrownpowder       1 (244)            ##STR233##      0.32(chloroform:methanol =3:1) 8.54(1H, d), 8.00(2H, d), 7.74(1H,     d),7.22(1H, s), 7.02(2H, d), 4.05(2H, t),2.54(3H, s) 2920, 2850, 1650,     1605,1595, 1530, 1505, 1465,1255, 1180, 1030, 840,760 475(M.sup.+)421,     233121 yellowbrownpowder       1 (245)            ##STR234##      0.32(chloroform:methanol =3:1) 8.53(1H, d), 7.98(2H, d), 7.73(1H,     d),7.20(1H, s), 7.02(2H, d), 4.05(2H, t),2.51(3H, s) 2930, 2850, 1650,     1605,1595, 1535, 1510, 1470,1260, 1180, 1035, 895,765 461(M.sup.+)407,     219121 yellowbrownpowder       1 (246)            ##STR235##      0.25(methylenechloride:methanol =5:1) 8.62(1H, d), 7.99(2H, d),     7.73(1H, d),7.18(1H, s), 7.01(2H, d),5.92-5.70(1H, m), 5.04-4.92(2H,     m),4.04(2H, t) 3460, 3070, 2930, 1650,1610, 1530, 1510, 1260 473(M.sup.+)2     31 whitepowder       1 (247)            ##STR236##      0.28(chloroformmethanol =5:1) 8.42(1H, s), 7.85(2H, d), 7.60(1H,     s),7.06(1H, s), 6.91(2H, d), 5.90-5.50(3H, m), 5.00-4.82(2H, m),     4.47(2H, d) 3600-2300, 1650, 1600,1535, 1505, 1450, 1370,1330, 1310,     1250, 1180 471(M.sup.+)351, 257243, 229 yellowpowder       1 (248)            ##STR237##      0.30(methylenechloride:methanol =4:1) 8.60(1H, brs), 8.03(2H, d),     7.78(1H,brs), 7.26(1H, s), 7.08(2H, d),4.21(2H, t), 3.72(2H, t),     2.68(3H, s) 3600-2300, 1650, 1600,1590, 1530, 1505, 1450,1255 446243,    2     24139, 121 paleyellowpowder       1 (249)            ##STR238##      0.30(methylenechloride:methanol =4:1) 8.73(1H, dd), 8.00(2H, d),     7.95(1H,dd), 7.51(1H, t), 7.24(1H, s), 7.03(2H, d), 4.05(2H, t) 3600-2300     , 1640, 1600,1580, 1520, 1500, 1420 445427, 255253, 121 palebrownpowder      1 (250)      ##STR239##      0.48(methylenechloride:methanol =5:1) 8.52(1H, d), 8.00(2H, d),     7.75(1H, d),7.22(1H, s), 7.04(2H, d), 3.55(2H, t) 3600-3150, 3060,     2920,2850, 1650, 1605, 1530,1510, 1450, 1370, 1260 473267 yellowbrownpowd     er       1 (251)            ##STR240##      0.31(methylenechloride:methanol =4:1) 8.57(1H, d), 7.98(2H, d),     7.72(1H, d),7.19(1H, s), 7.01(2H, d), 4.04(2H, t),3.54(2H, t) 3600-2300,     1650, 1600,1590, 1530, 1505, 1255 459,253, 181169, 121 palebrownpowder     1 (252)      ##STR241##      0.30(methylenechloride:methanol =5:1) 8.61(1H, d), 8.02(2H, d),     7.98(1H, d),7.54(1H, t), 7.05(2H, d), 4.08(2H, t),3.55(2H, t) 3450,     2920, 2850, 1650,1580, 1520, 1500, 1430,1290, 1250, 1180 459267 brownpowd     er       1 (253)            ##STR242##      0.45(chloroform:methanol =4:1) 8.69(1H, d), 8.00(2H, d), 7.89(1H,     d),7.24(1H, s), 7.04(2H, d), 5.96-5.64(3H, m), 5.60-4.90(2H, m),     4.60(2H, d),2.10-2.00(4H, m), 1.60-1.42(2H, m) 3600-2300, 1650, 1600,1580     , 1500, 1460, 1410,1365, 1255, 1175, 1030,1000, 890, 870, 760 49     3(M.sup.+)491,371  paleyellowpowder       1 (254)            ##STR243##      0.20(methylenechloride:methanol =5:1) 85.3(1H, dd), 7.94(2H, d),7.90(1H,      dd), 7.44(1H, t),7.28(1H, d), 7.26(1H, s),7.17(1H, s), 7.01(1H,     dd),6.96(2H, d), 3.99(2H, t),2.74(2H, t), 2.05(2H, m) 3450, 3070,     2920,1640, 1600, 1580,1520, 1500, 1470,1420, 1380, 1340,1290, 1250,      1     1180,030 307 brownpowder       1 (255)            ##STR244##      0.25(methylenechloride:methanol =5:1) 8.51(1H, d), 8.00(2H, dt),7.90.abo     ut.7.70(5H, m),7.54˜7.35(3H, m), 7.21(1H, s),7.05(2H, dt),     4.38(2H, t) 3650˜2200,1640, 1610, 1510,1470, 1260, 1180,1020, 890,     850,820, 760, 600 275, 155,121 paleyellowpowder       1 (256)            ##STR245##      0.26(methylenechloride:methanol =5:1) 8.55(1H, d), 8.00(2H, dt),7.76.abo     ut.7.72(1H, m), 7.35(1H, d), 7.32(1H, d),7.06(1H, dd), 7.01(2H, dt),4.04(     2H, t) 3650˜2100,1650, 1610, 1540,1510, 1470, 1390,1260, 1180,     1130,1030, 940, 890,860, 840, 770 307, 121 yellowpowder   1 (257)      ##STR246##      0.23(methylenechloride:methanol =5:1) 8.76(1H, dd), 8.01(2H, d),7.96(1H,      dd), 7.80(4H, m),7.47(4H, m), 7.23(1H, s),7.06(2H, d), 4.38(2H,     t),3.11(2H, t) 3400, 3050, 1650,1600, 1580, 1500,1430, 1370, 1340,1250,     1160, 1060,1020, 880, 850,810, 750 275 yellowpowder       1 (258)            ##STR247##      0.19(methylenechloride:methanol =5:1)   287 palebrownpowder   1 (259)      ##STR248##      0.23(methylenechloride:methanol =5:1)   287 brownpowder    1 (260)      ##STR249##      0.28(methylenechloride:methanol =5:1)   273, 121 darkyellowpowder

Example 1(301)-1(302)

By the same procedure as example 1, using with p-pentylcinnamic acid and8-amino-2-(5-tetrazolyl)-2,3-dihydro-1,4-dithianaphthalene hydrochlorideor 5-amino-2-(5-tetrazolyl) -2,3-dihydro-1,4-dithianaphthalenehydrochloride, following compounds having the following physical data,shown in table [X] were given. ##STR250##

                                      TABLE X                                     __________________________________________________________________________           6                                                                           Rf value in TLC                                                          Example                                                                            (developing                                                              No.  solvent) NMR (δppm)  IR (γcm.sup.-1)                                                                  Mass Appearance                      __________________________________________________________________________    1(301)                                                                             0.33     7.76(1H,d), 7.55(2H,d), 7.44-7.10                                                               3500-2300, 1660,                                                                       451(M.sup.+)                                                                       white                                (chloroform:                                                                           (3H,m), 7.24(2H,d), 6.73(1H,d),                                                                 1620, 1610, 1565,                                                                      408, 372                                                                           powder                               methanol 5.15(1H,m), 3.66(2H,m), 2.64(2H,t),                                                             1510, 1180, 980                                                                        357, 355                                  = 3:1)   0.90(3H,t)                 338, 201                             1(302)                                                                             0.23     7.72(1H,d), 7.51(2H,d), 7.22(2H,d),                                                             3500-2800, 1660,                                                                       201, white                                (chloroform:                                                                           7.60-7.10(3H,m), 6.71(2H,d),                                                                    1620, 1610, 1560,                                                                      198  powder                               methanol 5.40-5.26(1H,m), 3.56-3.40(2H,m),                                                               1510                                               = 3:1)   2.68(2H,t), 1.64(2H,t), 0.90(3H,t)                              __________________________________________________________________________

EXAMPLE 1(401)

By the same procedure as example 1, using with p-heptyloxybenzodithioicacid and 8-amino-2-(5-tetrazolyl)-1,4-benzodioxane hydrochloride,following compound having following physical data was given. ##STR251##

TLC: Rf 0.14 (chloroform: methanol=17:3); NMR: δ7.87 (2H, d), 7.77 (1H,m), 6.90(4H, m), 5.74 (1H, m), 4.58 (2H, m), 3.98 (2H, t), 1.78 (2H, m),1.30 (8H, m), 0.88 (3H, t); IR: ν3600-2400, 1600, 1495, 1450, 1255,1170,1090, 1005, 960, 830 cm⁻¹ ; Mass: m/e 453 (M⁺), 420, 354, 326, 235, 219,137, 121; Appearance: orange powder.

Example 1(501)-1(526)

By the same procedure as example 1, using a corresponding carboxylicacid and a corresponding amine, following compounds having the followingphysical data, shown in table [XI] were given.

    TABLE XI         Rf value in TLC     Example  (developing No. Formula solvent NMR     (δppm) IR (νcm.sup.-1) Mass Appearance              1(501)      ##STR252##      0.38(methylenechloride:methanol =4:1) 8.00(2H, d), 7.98(1H, d),         s     7.59(1H,), 7.50(1H, dd), 7.33(1H, t),7.01(2H, d), 4.04(2H, t) 3430,     2920, 2840,1640, 1610, 1530,1500, 1420, 1250 405(m.sup.+),205 whitepowder       1(502)     ##STR253##      0.34(methylenechloride:methanol =5:1) 8.00(2H, d), 7.97(1H, dd),     7.59(1H, s), 7.50(1H, dd), 7.32(1H,t), 4.04(2H, t), 7.01(2H, d) 3430,     2920, 2840,1640, 1610, 1530,1500, 1420, 1250 433(m.sup.+),233 whitepowder       1(503)     ##STR254##      0.38(methylenechloride:methanol =4:1) 8.00(2H, d), 8.00(1H, d),     7.58(1H, s), 7.50(1H, dd), 7.33(1H,t), 7.01(2H, d), 4.04(2H, t) 3430,     2920, 2840,1640, 1610, 1530,1500, 1420, 1250 419(m.sup.+),219 yellowpowde     r        1(504)     ##STR255##      0.35(methylenechloride:methanol =5:1) 7.99(2H, d), 7.97(1H, d),     7.58(1H, s), 7.49(1H, d), 7.31(1H,t), 7.00(2H, d), 4.04(2H, t) 3430,     2920, 2840,1640, 1610, 1530,1500, 1420, 1250 477(m.sup.+),247 brownpowder       1(505)     ##STR256##      0.38(methylenechloride:methanol =4:1) 7.94(2H, dd), 7.40(1H, d),     7.09(1H, dd), 6.97(2H, dd), 6.96(1H, t), 6.21(1H, dd), 4.02(2H, t),3.88(1     H, dd), 3.50(1H, dd) 3720, 3020, 2920,2850, 2730, 1640,1610, 1520,     1500,1440, 1310, 1250 407(m.sup.+),205 whitepowder       1(506)     ##STR257##      0.38(methylenechloride:methanol =5:1) 7.94(2H, dd), 7.34(1H, d),     7.11(1H, d), 6.98(2H, dd), 6.97(1H, t),6.22(1H, dd), 4.03(2H, t),     6.89(1H, dd), 6.50(1H, dd) 3270, 3020, 2920,2850, 2730, 1640,1610, 1520,     1500,1440, 1310, 1250 421(m.sup.+),219 whitepowder       1(507)     ##STR258##      0.38(methylenechloride:methanol =4:1) 7.94(2H, dd), 7.41(1H, d),     7.09(1H, dd), 6.98(2H, dd), 6.97(1H,t), 6.21(1H, dd), 4.02(2H, t),3.88(1H     , dd), 3.51(1H, dd) 3720, 3020, 2920,2850, 2730, 1640,1610, 1520,     1500,1440, 1310, 1250 435(m.sup.+),233 whitepowder       1(508)     ##STR259##      0.39(methylenechloride:methanol =4:1) 7.95(2H, dd), 7.41(1H, dd),     7.10(1H, dd), 6.99(2H, dd), 6.98(1H,t), 6.22(1H, dd), 4.04(2H, t),3.89(1H     , dd), 3.51(1H, dd) 3720, 3020, 2920,2850, 2730, 1640,1510, 1520,     1500,1440, 1310, 1250  449(m.sup.+),247 whitepowder       1(509)     ##STR260##      0.30(methylenechloride:methanol =5:1) 7.97(2H, d), 7.88(1H, d),     7.48(1H, d), 7.38˜7.14(7H, m),6.97(2H, d) 3700˜2100,     1540,1610, 1500, 1420,1390, 1350, 1300,1260, 1220, 1180,1070, 1020, 850,     740 453(m.sup.+),253,121 whitepowder       1(510)     ##STR261##      0.34(methylene chloride:methanol =5:1) 7.97(2H, d), 7.88(1H, d),     7.47(1H, d), 7.36˜7.23(2H, m), 7.00(2H, d), 5.98˜5.64(3H,     m), 5.10˜4.92(2H, m), 4.55(2H, d) 3600˜2100, 1640,1600,     1500, 1430,1390, 1350, 1300,1260, 1190, 1060,1000, 920, 840, 750     429(m.sup.+),299,201,121 whitepowder       1(511)     ##STR262##      0.40(methylenechloride:methanol =5:1) 8.00(2H, dt), 7.95(1H, dd),     7.49(1H, dd)7.31(1H, t), 7.29(1H, s), 7.00(2H, dt)4.05(2H, t) 3500˜     2100, 1640, 1610,1500, 1420, 1290, 1260,1200, 1110, 1050, 840,740     439(m.sup.+),239, 121 whitepowder       1(512)     ##STR263##      0.32(chloroform:methanol =5:1) 7.87(2H, d), 7.33(2H, m), 6.92(2H,     d),6.83(1H, t), 6.66(1H, dd), 3.98(2H, t),1.78(2H, m), 1.30(8H, m),     0.88(3H, m) 3650˜2400, 1640, 1605,1500, 1445, 1250 325,219     palebrownpowder       1(513)     ##STR264##      0.09(chloroform:methanol =9:1) 7.85(2H, d), 7.30(2H, m), 6.88(2H,     d),6.80(10H, t), 6.62(1H, d), 3.96(2H, d)1.77(2H, m), 1.34(6H, m),     0.88(3H, t) 3600-2500, 1630, 1600,1495, 1440, 1240 205,121 palebrownpowde     r       1(514)     ##STR265##      0.40(chloroform:methanol =5:1) 8.57(1H, s), 8.07(1H, d), 8.02(2H,     d),7.93(1H, d), 7.82(1H, d), 7.75(1H, d)7.54(1H, t), 7.30-7.18(5H,     m),6.98(2H, d), 4.40(2H, t) 3400, 2910, 1615, 1605,1560, 1480, 1380,     1300,1280, 1250, 1170, 1060,830, 750, 690 463(m.sup.+),420,253 yellowpowd     er       1(515)     ##STR266##      0.17(methylenechloride:ethyl acetate =2:1) 8.84(1H, dd), 8.40(1H, d),     8.28(1H, d)7.96(2H, d), 7.64˜7.56(2H, m), 6.99(2H,d), 5.80-5.56(3H,      m), 4.98-4.88(2H, m),4.50(2H, d), 2.12-1.94(4H, m), 1.52-1.36(2H, m)     3600-2300, 1635, 1600,1530, 1510, 1250, 1175,840, 760 548,440(m.sup.+),41     2, 332320 yellowpowder       1(516)     ##STR267##      0.18(methylenechloride:ethyl acetate =2:1) 8.93(1H, dd), 8.48(1H, d),     8.38(1H, d),8.04(2H, d), 7.76-7.64(2H, m), 7.32-7.16(5H, m), 7.04(2H,     d), 4.09(2H, t), 2.72(2H, t), 1.94-1.80(14H, m) 3600-2300, 1635,     1605,1530, 1505, 1250, 1170,835, 760  paleyellowpowder       1(517)     ##STR268##      0.47(methylenechloride:methanol =5:1) 8.03(1H, dd), 7.93(2H, d),     7.36-7.14(5H, m), 7.04(1H, t), 6.96(2H, d), 6.83(1H, dd), 5.45(1H, dd),     4.60(1H, dt),4.15(1H, dt) 3400-2300, 1645, 1610,1510, 1480, 1450,     1260,1060 485(m.sup.+),442, 439,411, 377,359 whitepowder   1(518)      ##STR269##      0.49(methylenechloride:methanol =5:1) 8.01(1H, dd), 7.93(2H, d),     7.03(1H, t),6.97(2H, d), 6.82(1H, dd), 5.96-5.60(2H, m), 5.45(1H, dd),     5.07-6.90(2H, m),4.62(1H, dt), 4.15(1H, dt), 4.53(2H, d) 3260, 3200-2300,      1645,1610, 1500, 1475, 1450,1255, 461, 405,353, 341 whitepowder     1(519)      ##STR270##      0.18(methylenechloride:ethyl acetate =2:1) 8.98(1H, dd), 8.49(1H, d),     8.38(1H, d),8.06(2H, d), 7.78-7.66(2H, m), 7.06(2H,d), 4.10(2H, t),     3.58(2H, t), 2.00-1.78(4H, m), 1.70-1.50(4H, m) 3600-2300, 1635,     1600,1530, 1510, 1255, 1175,840, 765  yellowpowder       1(520)     ##STR271##      0.40(chloroform:methanol =4:1) 8.00(1H, dd), 7.93(2H, d), 7.04(1H,     t),6.95(2H, d), 6.83(1H, dd), 5.81(1H, m)5.45(1H, dd), 5.00(2H, m),     4.60(1H, m),4.18(1H, m), 4.00(2H, t), 2.74(2H, m),2.07(2H, m), 1.80(2H,     m), 1.42(6H, m) 3200, 2930, 2860, 1605,1565, 1530, 1505, 1470,1450,     1250, 1060 463(m.sup.+),407, 231, 121, 93 yellowpowder       1(521)     ##STR272##      0.55(methylenechloride:methanol =5:1) 7.88(2H, d), 7.54(1H, m),     7.34-7.12(5H, m), 7.00-6.86(4H, m), 5.73(1H, dd),4.02(2H, t) 3300-2200,     1610, 1530,1510, 1460, 1260 468(m.sup.+),441, 426,413, 395,253 whitepowde     r       1(522)     ##STR273##      0.42(methylenechloride:methanol =5:1) 7.88(2H, d), 7.50(1H, m),     7.00-6.88(4H, m), 5.92-5.66(2H, m), 5.06-4.90(2H, m), 4.02(2H, t)     3400-2300, 1610, 1570,1530, 1505, 1460, 1260 447(m.sup.+),253, 231     whitepowder       1(523)     ##STR274##      0.25(methylenechloride:methanol =5:1) 7.91(2H, d), 7.35-7.10(6H, m),     6.95(2H, d), 6.94(1H, t), 6.78(1H, dd),4.03(2H, t) 3400, 3100-2300,      1     1660,610, 1580, 1530, 1500,1450, 1250 253, 225,121 palebrownpowder     1(524)      ##STR275##      0.25(methylenechloride:methanol =5:1) 8.15(1H, d), 7.78(1H, d),     7.65-7.20(8H, m), 6.90(1H, d), 2.66(2H, t), 0.92(3H, t) 3300, 1630,     1530, 1200,740 401(m.sup.+),343, 372358, 344 palebrownpowder   1(525)      ##STR276##      0.27(chloroform:methanol =3:1) 7.68(1H, d), 7.44(2H, d), 7.40(1H,     s),7.25(1H, d), 7.18(2H, d), 6.90(1H, t),6.73(1H, d), 6.65(1H, d),     2.62(2H, t),1.62(2H, m), 1.20-1.45(4H, m), 0.89(3H, t), 3250, 2930,     2850, 1660,1620, 1600, 1525, 1445,1340, 1255, 1180, 1070,980, 825, 765,     710 405, 349,336, 325,306, 201,131, 115 palebrownpowder   1(526)      ##STR277##      0.40(methylenechloride:methanol =5:1) 8.31(1H, s), 7.94(2H, d),7.86(1H,     d), 7.72(1H, d),7.68(1H, d), 7.57(1H, d),7.41(1H, t), 6.90(2H, d),3.96(2H     , t), 3.55(2H, t) 3400, 2920, 1615,1605, 1480, 1300,1250, 1170, 830750     239 yellowpowder

EXAMPLE 2

Synthesis of8-(3-methoxy-4-pentyloxycinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane##STR278##

Sodium azide (490 mg) and pyridinium chloride (870 mg) were added to asolution of 8-(3-methoxy-4-pentyloxycinnamoyl)amino-1,4-benzodioxane(560 mg; synthesized in reference example 2) in dry dimethylformamide (3ml). In an atmosphere of argon, the solution was stirred for 1.5 hrs at100° C. The reaction solution cooled to room temperature was pouredinto1N hydrochloric acid, and the mixture was extracted with ethyl acetate.The extract was washed with water and a saturated aqueous solution ofsodium chloride, dried, and then concentrated under reduced pressure.The residue was recrystallized from ethyl acetate to give the titlecompound (390 mg) having the following physical data:

TLC: Rf 0.10 (chloroform: methanol=5:1); NMR: δ7.69(1H, d), 7.68(1H, s),7.05-7.25(2H, m), 6.80-7.00(2H, m), 6.74(1H, m), 6.65(1H, d),5.73(1H,m), 4.69(1H, dd), 4.51(1H, dd), 4.05 (2H, t), 3.92 (3H, s), 1.87(2H, m), 1.30-1.55 (4H, m), 0.94 (3H, t); IR: ν2940, 2850, 1655, 1600,1540, 1505, 1450, 1260 cm⁻¹ ; Mass m/e 465(M⁺), 247, 177, 145.

EXAMPLE 2(1)-2(46)

By the same procedures as reference example 1, 2 and example 1, using acorresponding carboxylic acid and 3-aminopyrocatechol, followingcompoundshaving the following physical data, shown in table [XII] weregiven. ##STR279##

    TABLE XII       Example  Substituent R in the Rf value in TLC     No. general formula     (Io) (developing solvent) NMR (δ ppm) IR (ν cm.sup.-1) Mass     Appearance              2(1)      0.28(methylene chloride:methanol = 5:1) 7.72(1H, d), 7.66(1H, m),     7.46(2H, d),7.18(2H, d), 6.88(1H, t), 6.74(1H, d),6.72(1H, dd), 5.67(1H,     dd), 4.65(1H, dd),2.62(2H, t), 1.62(2H, m), 1.20-1.45(4H, m), 0.88(3H,     t) 3250, 2930, 2860,1660, 1610, 1540,1260, 1200, 1100, 965,  775,  715     419 (M.sup.+)219, 201131 white powder   2(2)      ##STR280##      0.3(methylene chloride:methanol = 4:1) (DMSO-d.sub.6)9.24(1H, s),     7.78(1H, d), 7.56(1H, d), 7.15-7.30(2H, m), 7.00(1H, d), 6.94(1H, d),     6.87(1H, t), 6.68(1H, dd), 6.00(1H, dd), 4.68(1H, dd), 4.49(1H, dd),     3.82(3H, s), 3.80(3H, s) 1660, 1600, 1540,1510, 1480, 1450 409 (M.sup.+)3     66, 353315, 296258, 233219, 191 pale yellow powder   2(3)      ##STR281##      0.3(methylene chloride:methanol = 5:1) 8.02(1H, s), 7.80(1H, d),     7.35-7.50(2H,m), 7.24(1H, d), 7.20-7.35(2H, m), 6.83(1H, t), 6.72(1H,     d), 6.62(1H, d), 5.73(1H, m), 4.72(1H, dd), 4.56(1H, dd) (liquid     film)1650,1610, 1540, 1480,1450 447 (M.sup.+)419, 404391, 353334, 229219     white powder   2(4)      ##STR282##      0.3(methylene chloride:methanol = 5:1) 8.46(1H, s), 7.8-8.1(4H, m),     7.5-7.7(3H, m), 6.94(1H, t), 6.78(1H, dd),5.78(1H, dd), 4.52-4.74(2H, m) 1     620, 1605, 1540,1500, 1460, 1430 373 (M.sup.+ )331, 296223, 155 white     powder   2(5)      ##STR283##      0.3(methylene chloride:methanol = 5:1) (CDCl.sub.3)7.85(1H, d),     7.4-7.(2H, m), 7.34(1H,s,),7.15-7.30(2H, m), 6.7-6.9(3H, m),6.56(1H, d),     5.78(1H, m), 4.98(1H, dd),4.50(1H, dd), 2.68(2H, q), 1.25(3H, t) 1650,     1605, 1530,1475, 1450 377 (M.sup.+)219, 159129 pale yellow powder   2(6)      ##STR284##      0.3(methylene chloride:methanol = 5:1) 7.64(1H, d), 7.40-7.55(2H, m),     7.10-7.25(2H, m), 6.98(1H, dd), 6.86(1H, t),6.76(1H, dd), 6.57(1H, d),     5.78(1H, m),4.90(1H, d), 4.52(1H, d) 1660, 1605, 1530,1480, 1445 391     (M.sup.+)219, 173131, 115 pale yellow powder   2(7)      ##STR285##      0.3(methylene chloride:methanol = 5:1) 7.82(1H, d), 7.40- 7.55(2H, m),     7.1-7.25(2H, m), 7.11(1H, d), 6.85(1H, t),6.74(1H, dd), 6.59(1H, d),     5.76(1H, m),4.81(1H, d), 4.54(1H, d) 1660, 1605, 1535,1480, 1450 405     (M.sup.+)219, 187131 pale yellow powder   2(8)      ##STR286##      0.3(methylene chloride:methanol = 5:1) 7.76(1H, d), 7.52(1H, d),     7.40(1H, s),7.32(1H, d), 7.20(1H, d), 6.89(1H, t),6.73(1H, dd), 6.65(1H,     d), 5.72(1H, dd),4.64(1H, dd), 4.54(1H, dd) 1650, 1605, 1540,1470, 1450     389 (M.sup.+)276, 219171, 143128, 115 pale brown powder   2(9)      ##STR287##      0.45(methylene chloride:methanol = 5:1) (CDCl.sub.3)7.23(5H, m),     6.77(3H, m), 5.75(1H, t),4.93(1H, dd), 4.46(1H, dd), 3.76(2H, s),2.61(2H,      t), 1.61(2H, m), 1.33(4H, m),0.88(3H, t) 3600-2300, 1660,1620, 1605,     1550,1465, 1270, 1205,1090,  780 407 (M.sup.+)219, 188 161 yellow powder       2(10)     ##STR288##      0.20(chloroform:methanol = 4:1) (CDCl.sub.3)8.0(1H, s), 7.80(2H, d),     6.7-7.1(5H, m),5.75(1H, m), 4.85(1H, dd), 4.50(1H,dd), 4.00(2H, t) 2950,     1640, 1610,1540, 1510, 1460,1260, 1180, 1100, 845,      780 409 (M.sup.+)366, 259191, 121 white powder       2(11)     ##STR289##      0.20(chloroform:methanol = 4:1) 7.86(1H, s), 7.76(1H, d), 7.39(2H,     d),7.17(1H, d), 6.70(2H, d), 6.76(1H, t),6.66(1H, dd), 6.48(1H, d),     5.69(1H, dd),4.66(1H, dd), 4.51(1H, dd), 3.92(2H,t) 2950, 1655, 1600,1535     , 1505, 1460,1250, 1165, 1100, 960,  820,  770 435 (M.sup.+)392, 259217,     147119 pale yellow powder       2(12)     ##STR290##      0.55(methylene chloride:methanol = 4:1) 8.09(1H, d), 7.77(2H, m),     7.23(3H, m),6.92(1H, t), 6.71(2H, m), 5.73(1H, dd),4.69(1H, dd),     4.49(1H, dd), 2.78(2H, t),1.58(2H, m), 1.34(4H, m), 0.88(3H, t) 3600-2200     , 1660,1620, 1605, 1550,1450, 1270, 1200,1105,  970,  780, 760 419     (M.sup.+)219, 201 white powder       2(13)     ##STR291##      0.71(methylene chloride:methanol = 4:1) 7.72(1H, d), 7.76(1H, dd),     7.28(4H, m),6.90(1H, t), 6.76(1H, d), 6.73(1H, dd),5.72(1H, dd),     4.67(1H, dd), 4.49(1H, dd),2.61(2H, t), 1.62(2H, m), 1.26(10H, m),0.87(3H     , t) 3600-2300, 1660,1650, 1555, 1460,1260, 1190, 1100, 980,  960,  775     461 (M.sup.+)243, 219 white powder       2(14)     ##STR292##      0.30(methylene chloride:methanol = 4:1) 7.76(1H, d), 7.52(1H, d),     7.47(2H, d),7.19(2H, d), 6.90(1H, t), 6.75(1H, dd),6.67(1H, d), 5.72(1H,     dd), 4.70-4.50(2H, m) 3300-2300, 1670,1625, 1555, 1470 433 (M.sup.+)219,     215 white crystal       2(15)     ##STR293##      0.30(methylene chloride:methanol = 4:1) 7.75(1H, d), 7.52(1H, d),     7.46(2H, d),7.17(2H, d), 6.88(1H, t), 6.75(1H, dd),6.66(1H, d), 5.70(1H,     dd), 4.80-4.45(2H, m) 3300-2300, 1675,1635, 1620, 1560,1465, 1270 475     (M.sup.+)257, 219 white crystal       2(16)     ##STR294##      0.30(methylene chloride:methanol = 5:1) 7.76(1H, d), 7.53(1H, d),     7.46(2H, d),7.18(2H, d), 6.89(1H, t), 6.74(1H, dd),6.68(1H, d), 4.72(1H,     dd) 3500-2300, 1665,1630, 1615, 1550,1460, 1260 461 (M.sup.+)243, 219     white crystal       2(17)     ##STR295##      0.52(methylene chloride:methanol = 17:3) 7.72(3H, m), 7.33(2H, m),     6.88(1H, t),6.73(1H, dd), 5.60(1H, dd), 4.51(2H, m),2.65(2H, t),     1.62(2H, m), 1.28(10H, m),0.87(3H, t) 3650-2700, 2920,2840, 1650,     1605,1520, 1450, 1260,1080,  900,  870 218, 217 pale yellow powder     2(18)      ##STR296##      0.40(methylene chloride:methanol = 17:3) 7.98(1H, m), 7.60(1H, m),     7.39(1H, m),7.30(3H, m), 6.94(1H, t), 6.79(1H, dd),5.74(1H, m), 4.62(2H,     m), 2.83(2H, t),1.65(2H, m), 1.28(4H, m), 0.86(3H, m) 3600-2300,     1660,1640, 1610, 1520,1480, 1450, 1260,1100,  775 393 (M.sup.+)219, 175     yellow powder       2(19)     ##STR297##      0.10(chloroform:methanol = 5:1) (CDCl.sub.3)7.92(1H, s), 7.40-7.60(2H,     m), 7.10-7.25(1H, m), 6.70-7.00(4H, m), 5.77(1H, t), 4.97(1H, dd),     4.50(1H, dd), 4.07(2H, t), 3.94(3H,s), 1.88(2H, m), 1.30-1.60(4H, m),     0.94(3H, t) 2930, 1630, 16001580, 1540, 1505,1460, 1340, 1265 439,     341221, 151123 white powder       2(20)     ##STR298##      0.10(chloroform:methanol = 5:1) (CDCl.sub.3)7.98(1H, s), 7.30-7.55(3H,     m), 7.05-7.20(1H,m), 6.70-7.00(3H, m), 5.77(1H, t), 4.95(1H,dd),     4.50(1H, dd), 4.02(2H, t), 1.82(2H, m),1.25-1.60(4H, m), 0.94(3H, t)     2950, 1635, 1605,1580, 1540, 1450,1335, 1260, 1230,1085,  780 409     (M.sup.+)259, 191138, 121 93 white powder       2(21)     ##STR299##      0.10(chloroform:methanol =      5:1) (CDCl.sub.3)7.70-7.90(2H, m), 6.50-7.50(9H, m),5.74(1H, m),     4.80(1H, m), 4.52(1H, m),3.93(2H, t), 1.78(2H, m), 1.20-1.60(4H, m),     0.93(3H, t) 2950, 2860, 1660,1600, 1540, 1450,1260, 1195, 1100,1050,     970,  780 435 (M.sup.+)219, 217191, 175 147 white powder   2(22)      ##STR300##      0.10(chloroform:methanol = 5:1) (CDCl.sub.3) 10.03(1H, s), 8.35(1H,     dd), 7.50(1H, m), 7.25(1H, s), 7.15(1H, m), 7.03(1H,d), 6.70-6.95(3H,     m), 5.75(1H, t), 4.98(1H,dd), 4.50(1H, dd), 4.20(2H, t), 1.90(2H,     m)1.20-1.60(4H, m), 0.90(3H, t) 3320, 2950, 2860,1640, 1610, 1545,1460,     1300, 1235,1085,  775,  760 409 (M.sup.+)367, 191149, 121 white powder     2(23)      ##STR301##      0.10(chloroform:methanol = 5:1) (CDCl.sub.3) 8.11(1H, d), 7.40-7.60(2H,     m), 7.20-7.40(1H, m), 7.02(1H, d), 6.65-6.95(5H, m),5.76(1H, t),     4.85(1H, m), 4.52(1H, m), 4.00(2H, t), 1.85(2H, m), 1.20-1.60(4H,     m),0.92(3H, t) 2950, 2860, 1655,1610, 1540, 1480,1450 435 (M.sup.+)407,     348341, 219217, 147 white powder       2(24)     ##STR302##      0.30(chloroform:methanol = 5:1) 7.77(1H, d), 7.65(1H, d), 7.50(2H,     d),7.22(2H, d), 6.93(1H, t), 6.76(1H, dd),6.73(1H, d), 5.74(1H, dd),     4.69(1H, dd),4.54(1H, dd) 3300-2500, 1670,1630, 1620, 1555,1460, 1260     489 (M.sup.+)271, 219 white crystal       2(25)     ##STR303##      0.37(methylene chloride:methanol = 17:3) 7.86(1H, s), 7.68(1H, dd),     7.42(4H, m),6.92(1H, t), 6.77(1H, dd), 5.75(1H, dd),4.61(2H, m),     2.98(2H, t), 1.67(2H, m),1.38(4H, m), 0.89(3H, t) 3600-2300, 1640,1610,     1540, 1455,1340, 1270, 1260,1090,  770 425 (M.sup.+)207 white powder     2(26)      ##STR304##      0.47(methylene chloride:methanol = 17:3) 7.81(1H, d), 7.26(4H, m),     6.91(1H, t),6.77(1H, dd), 5.75(1H, dd), 4.69(1H, dd),4.58(1H, dd),     2.92(2H, t), 1.60(2H, m),1.32(4H, m), 0.86(3H, t) 3600-2300, 1630,1610,     1540, 1460,1320, 1260, 1090, 780,  740 425 (M.sup.+)219, 207 yellow     powder       2(27)     ##STR305##      0.14(chloroform:methanol = 4:1) (CDCl.sub.3)7.92(1H, s), 7.85(2H, d),     7.30(2H, d), 6.70-7.00(3H, m), 5.76(1H, t), 4.95(1H, dd), 4.50(1H, dd),     2.70(2H, t), 1.50-1.80(2H, m),1.20-1.50(2H, m), 0.94(3H, t) 2930, 2850,     1610,1535, 1460, 1330,1280, 1260, 1090 379 (M.sup.+)229, 161118,  917     white powder       2(28)     ##STR306##      0.14(chloroform:methanol = 4:1) (CDCl.sub.3)8.12(1H, s), 7.82(2H, d),     7.26(2H, d), 6.70-7.10(3H, m), 5.72(1H, t), 4.83(1H, dd), 4.47(1H, dd),     2.66(2H, t), 1.62(2H, m), 1.10-1.45(6H, m), 0.88(3H, t) 2930, 2850,      1     1640,610, 1545, 1455,1330, 1280, 1260,1090,  770 407 (M.sup.+ )257,     189118,  91 white powder       2(29)     ##STR307##      0.14(chloroform:methanol = 4:1) (CDCl.sub.3)8.04(1H, s), 7.83(2H, d),     7.28(2H, d), 6.70-7.10(3H, m), 5.74(1H, t), 4.85(1H, dd), 4.48(1H, dd),     2.67(2H, t), 1.63(2H, m), 1.10-1.45(8H, m), 0.88(3H, t) 2930, 2850,      1     1640,620, 1550, 1460,1340, 1280, 1270,1100 421 (M.sup.+)271, 203131, 118 9     1 white powder       2(30)     ##STR308##      0.14(chloroform:methanol = 4:1) (CDCl.sub.3)8.07(1H, s), 7.83(2H, d),     7.27(2H, d), 6.70-7.10(3H, m), 5.74(1H, t), 4.85(1H, dd), 4.48(1H, dd),     2.67(2H, t), 1.63(2H, m), 1.10-1.45(10H, m), 0.88(3H, t) 2930, 2850,     1640,1620, 1550, 1460,1340, 1280, 1270,1100 435 (M.sup.+)285, 217131,     118 91 pale yellow powder       2(31)     ##STR309##      0.14(chloroform:methanol = 4:1) (CDCl.sub.3) 7.81(1H, d), 7.50(1H, s),     7.47(2H, d), 6.70-7.10(5H, m), 6.48(1H, d),5.76(1H, m), 4.86(1H, dd),     4.70(2H, m),4.53(1H, dd), 2.22(2H, t), 1.60(1H, s), 1.50(2H, m),     1.15-1.45(4H, m), 0.87(3H, t) 2930, 2860, 1660,1600, 1540, 1505,1450,     1260, 1170, 1100, 1000,  960,  825,  775 473 (M.sup.+)255, 219147, 119     white powder       2(32)     ##STR310##      0.46(methylene chloride:methanol = 17:3) 7.69(1H, d), 7.44(1H, m),     7.28(3H, m)6.86(1H, t), 6.71(1H, dd), 6.68(1H, d),5.69(1H, t), 4.60(2H,     m), 2.91(2H, t),1.64(2H, m), 1.36(4H, m), 0.88(3H, t) 3600-2200,     1650,1605, 1540, 1450,1260, 1190, 1090, 960,  780,      770 451 (M.sup.+)233, 219 white powder       2(33)     ##STR311##      0.36(methylene chloride:methanol = 17:3) 8.29(1H, d), 7.51(2H, m),     7.28(3H, m),6.86(1H, t), 6.71(1H, dd), 6.62(1H, d),5.71(1H, dd),     4.60(2H, m), 2.88(2H, t),1.62(2H, m), 1.36(4H, m), 0.88(3H, t) 3600-2300,      1660,1620, 1555, 1450,1265, 1200, 1105, 970,  780,      760 451 (M.sup.+)348 pale yellow powder       2(34)     ##STR312##      0.49(methylene chloride:methanol = 17:3) 7.74(1H, d), 7.48(3H, m),     7.24(3H, m),6.87(1H, t), 6.72(1H, dd), 6.67(1H, d),5.70(1H, m), 4.59(2H,     m), 1.26(6H, d) 3600-2300, 1640,1610, 1540, 1450,1255, 1200, 1090, 960,     820 391 (M.sup.+)219, 173 white powder       2(35)     ##STR313##      0.62(methylene chloride:methanol = 17:3) 7.74(1H, d), 7.43(3H, m),     7.22(2H, d),6.85(1H, t), 6.70(1H, dd), 6.66(1H, d),5.68(1H, m), 5.59(2H,     m), 2.48(2H, d),1.86(1H, m), 0.90(6H, d) 3600-2300, 1655,1610, 1540,     1455,1260, 1100,  965, 835,  770,  710 405 (M.sup.+)219, 187 white     powder       2(36)     ##STR314##      0.10(chloroform:methanol = 4:1) (CDCl.sub.3)8.10(1H, s), 7.85(2H, d),     6.60-7.10(5H,m), 5.50-6.00(3H, m), 4.80(1H, dd),4.30-4.70(3H, m),     2.10(2H, m),1.10-1.60(6H, m), 0.89(3H, t) 2930, 2860, 2730,1630, 1600,     1540,1495, 1450, 1310,1250, 1170, 1090, 990,  835,                       3      765 559 449 (M.sup.+)29, 121 pale brown powder       2(37)     ##STR315##      0.10(chloroform:methanol = 4:1) (CDCl.sub.3)7.80(1H, d), 7.66(1H, s),     7.42(2H, d), 7.08(1H, d), 6.65-7.10(4H, m), 6.48(1H, d), 5.55-6.00(3H,     m), 4.75(1H, dd), 4.40-4.65(3H, m),2.08(2H, m), 1.10-1.60(6H, m),     0.88(3H, t) 2930, 2860, 1680,1600, 1540, 1510,1460, 1265, 1180,1100,     970,  830, 780 585,475 (M.sup.+)329, 147 white powder       2(38)     ##STR316##      0.57(chloroform:methanol = 4:1) 7.74(1H, d), 7.59(1H, d), 7.47(2H,     d),7.19(1H, d), 6.90(1H, t), 6.73(1H, dd),6.68(1H, dd), 5.71(1H, dd),     4.66(1H, dd),4.52(H, dd), 2.63(2H, m), 2.40(1H, m),1.52(2H, m), 0.94(6H,     d) 3600-2300, 1660,1610, 1540, 1460,1265, 1200, 1100,      965 419 (M.sup.+)219, 201 white powder       2(39)     ##STR317##      0.42(methylene chloride:methanol = 17:3) 7.30(1H, m), 7.03(1H, m),     6.84(1H, t),6.72(1H, d), 6.03(1H, d), 5.70(1H, m),4.60(1H, m), 2.23(2H,     m), 1.36(22H, m),0.88(3H, t) 3600-2200, 2900, 2835,1675, 1660, 1610,     1530,1460, 1440, 1260, 1205,1100, 1040,  970,  910,  860,  770,  710 455     (M.sup.+)237, 219 white powder       2(40)     ##STR318##      0.10(chloroform:methanol = 4:1) (CDCl.sub.3 + DMSO-d.sub.6)7.52(2H, d),     6.91(2H, d), 6.91(1H, t),6.70(1H, d), 6.68(1H, d), 5.70(1H, dd),4.78(1H,     dd), 4.40(1H, dd), 3.96(2H, t),1.83(2H, m) 2970, 2680, 1660,1600, 1540,     1510,1455, 1260, 1170,1100,  970,  825, 770,  710,  560, 515 407     (M.sup.+)219, 189147, 119 91 white powder       2(41)     ##STR319##      0.10(chloroform:methanol = 4:1) (CDCl.sub.3 + DMSO-d.sub.6)8.68(1H, s),     7.86(1H, d), 7.72(1H, d), 7.52(2H, d), 6.91(1H, t), 6.90(2H, d),         d     6.71(1H,), 6.67(1H, d), 5.70(1H, dd), 4.78(1H, dd),4.40(1H, dd),     4.00(2H, t) 2970, 2870, 1660,1600, 1540, 1510,1460, 1260, 1190,1175,     1100,   970, 830,  770,  715, 565 421 (M.sup.+)219, 203147, 119 91,  69     white powder       2(42)     ##STR320##      0.10(chloroform:methanol = 4:1) (CDCl.sub.3 + DMSO-d.sub.6)8.62(1H, s),     7.81(1H, d), 7.72(1H, d), 7.50(2H, d), 6.90(1H, t), 6.88(2H, d),         d     6.70(1H,), 6.65(1H, d), 5.68(1H, dd), 4.76(1H, dd),4.40(1H, dd),     3.98(2H, t) 2920, 2850, 1660,1600, 1540, 1510,1460, 1260, 1170,1100,     970,  910, 825, 770,  715,  565, 520 477 (M.sup.+)259, 219189, 147119     pale yellow powder       2(43)     ##STR321##      0.30(methylene chloride:methanol = 5:1) 7.52(1H, s), 7.30(2H, d),     7.20(2H, d),7.15(1H, dd), 6.89(1H, t), 6.76(1H, dd),5.78(1H, dd),     4.80(1H, dd), 4.52(1H, dd) 3250, 3200-2300,1640, 1600, 1550,1530, 1490,     1470,1110,  780 433 (M.sup.+)286, 281215 white powder       2(44)     ##STR322##      0.35(chloroform:methanol = 4:1) 7.88(2H, d), 7.70(2H, d), 7.51(1H,     dd),6.96(2H, m), 6.76(1H, dd), 6.04(1H, d),5.76(1H, t), 4.61(2H, m),     2.25(2H, m),1.49(2H, m), 1,34(4H, m), 0.89(3H, t) 3600-2300, 1650,1610,     1520, 1445,1260, 1110,  980, 850,  780 462 (M.sup.+)419, 244 pale brown     crystal       2(45)     ##STR323##      0.18(chloroform:methanol =      4:1) 7.87(1H, dd), 7.82(2H, d), 7.30-7.10(5H, m), 6.92(2H, d), 6.84(1H,     t),6.69(1H, dd), 5.57(1H, dd), 4.62(1H, dd),4.45(1H, dd) 3600-2300,      1     1650,610, 1535, 1510,1460, 1260 471 (M.sup.+)383, 253121 white powder     2(46)      ##STR324##      0.20(methylene chloride:methanol = 5:1) 7.89(1H, dd), 7.83(2H, d),     6.96(2H,brd), 6.86(1H, t), 6.70(1H, dd),5.96-5.54(3H, m), 4.65(1H,     dd),4.52(2H, d), 4.46(1H, dd) 3700-2200, 2940,1640, 1600, 1540,1510,     1460, 1340,1260, 1180, 1100,1000,  980,  850, 780 449 (M.sup.+)339,     231219, 121 white powder

EXAMPLE 2(101)-2(107)

By the same procedures as reference example 1, 2 and example 2, using acorresponding carboxylic acid and 3-aminopyrocatechol which havecorresponding substituents R² and R³, following compounds havingthefollowing physical data, shown in table [XIII] were given. ##STR325##

    TABLE XIII       Example Substituent R, R.sup.2, R.sup.3 Rf value in TLC     No. in the     general formula (Ip) (developing solvent) NMR (δppm) IR (νcm.sup     .-1) Mass Appearance              2(101)      0.38(methylene chloride:methanol = 3:1) (CDCl.sub.3)7.92(1H, d),     7.52(2H, d), 7.22(2H, d),7.00(1H, d), 6.96-6.74(3H, m), 5.77(1H, m),     5.04(1H, d), 4.50(1H, dd),3.59(3H, s), 0.88(3H, t) (liquid film)3500-2300     , 1650,1590, 1480, 1275,1100 433 (M.sup.+)233, 201 pale brown solid     2(102)      ##STR326##      0.29(chloroform:methanol =  3:1) 8.03(1H, d), 7.71(1H, d), 7.48(2H,     d),7.18(2H, d), 6.81(1H, d), 6.71(1H, d),4.79(1H, dd), 4.74(1H, dd),     (     4.351H, dd) (liquid film)3600-3100, 1690,1610, 1540, 1460,1440, 1220     455, 453255, 253201 pale brown oil       2(103)     ##STR327##      0.30(chloroform:methanol = 3:1) 7.83(2H, d), 7.68(1H, d), 7.48(2H,     d),7.17(2H, d), 6.86(1H, d), 6.51(1H, d),5.51(1H, dd), 4.70(1H, dd),     (     4.281H, dd) 3600-2500, 1680,1620, 1610, 1540,1460 201, 189175 white     solid       2(104)     ##STR328##      0.25(chloroform:methanol = 3:1) 7.81(2H, d), 7.65(1H, d), 7.38(1H,     d),6.77(1H, d), 5.75(1H, dd), 4.74-4.50(2H, m), 0.88(3H, t) 3300,     3200-2300,1640, 1620, 1545,1470, 1430, 1100, 860,  740 427 (M.sup.+)243,     175 brown crystal       2(105)     ##STR329##      0.44(methylene chloride:methanol = 17:3) (CD.sub.3 OD)7.20(3H, m),     6.74(4H, m), 5.22(1H, m),4.40(2H, m), 3.92(2H, m), 3.36(3H, s),1.73(2H,     m),1.31(10H, m),0.90(3H, t) 3600-2300, 1605, 1590,1470, 1420, 1380,      1     1300,260, 1180, 1090, 1060,1040, 1015,  895,  840, 760 465 (M.sup.+)301,     233 white powder       2(106)     ##STR330##      0.41(methylene chloridemethanol = 17.3) (CD.sub.3 OD)7.20(3H, m),     6.73(4H, m), 5.70(2H, m),5.20(1H, m), 4.41(3H, m),3.36(3H, s),2.65(2H,     m), 1.30(6H, m), 0.88(3H, t) 3600-2300, 1610, 1595, 1470, 1420, 1380,     1300,1250, 1220, 1175, 1090,1040,  990,  960,  895, 840,  760 463     (M.sup.+) 343, 233231 white powder       2(107)     ##STR331##      0.32(chloroform:methanol = 4:1) 7.99(2H, d), 7.63(1H, d), 7.00(2H,     d),6.88(1H, d), 5.97(1H, m), 4.60(2H, m),4.05(2H, t), 3.88(3H, s),     1.83(2H, m),1.32(10H, m), 0.90(3H, t) 3600-2300, 1690, 1655,1610, 1500,     1470, 1280,1260, 1080,  910,  840, 780,  760 509 (M.sup.+)449, 329233     white powder

EXAMPLE 2(201)-2(204)

By the same procedure as reference example 1, 2 and example 2, usingwith acorresponding carboxylic acid and 3-aminopyrocatechol which havecorresponding substituent R³, following compounds having followingphysical data were given. ##STR332##

TLC: Rf 0.21 (chloroform: methanol=3:1); NMR δ8.03(1H, d), 7.70(1H, d),7.48(2H, d), 7.20 (2H, d), 6.71 (1H, d), 6.65 (1H, d), 5.57(1H, s),4.70-4.40(2H, m), 2.62(2H, t); IR: ν3700-3000, 1680, 1625, 1610 ,1535,1470, 1440 cm⁻¹ ; 1Mass: m/e 201, 179, 162; Appearance: whitepowder. ##STR333##(The substituting position of tetrazolyl was notknown.)

TLC: Rf 0.22 (methylene chloride: methanol=5:1); NMR: δ8.21(1H, d), 7.74(1H, d), 7.57 (1H, d), 7.49 (2H, d), 7.20 (2H, d), 6.62 (1H, d), 5 . 74(1H, dd), 4.89(1H, dd), 4.54 (1H, dd); IR : ν3370, 3200-2300, 1695,1630, 1610, 1520, 1430, 1270, 1140 cm⁻¹ ; Mass: m/e 477(M⁺), 291, 201;Appearance: white crystal. ##STR334##less polar compound:

TLC: Rf 0.18 (methylene chloride: methanol=5:1); NMR (CDCl₃): δ9.88 (1H,s), 7.81 (1H, d), 7.45 (3H, s), 7.18 (2H, s), 6.69(1H, s), 6.64 (1H, d),6.04(1H, s), 5.60 (1H, s), 4.50 (1H, s), 3.84 (3H, s), 0.88 (3H, t); IR:ν3600-2300, 1695, 1630, 1610, 1515, 1470, 1280 cm⁻¹ ; Mass: m/e 477(M⁺),446, 291, 201; Appearance: white crystal.

more polar compound:

TLC: Rf 0.12 (methylene chloride: methanol=5:1); NMR (CDCl3): δ9.44 (1H,s), 7.46 (1H, s), 7.25 (1H, s), 7.13 (2H, s), 6.88 (2H, s),6.60-6.30(2H, s), 5.20 (1H, s), 4.20-3.60 (2H, s), 3.72 (3H, s), 0.83(3H,t); IR: ν3600-3000, 1695, 1630-1610, 1520, 1480, 1280 cm⁻¹ ; Mass:m/e 477(M⁺), 446, 291, 201; Appearance: white crystal.

EXAMPLE 2(301)

By the same procedure as example 2, using with8-(p-pentylcinnamoyl)amino-1,4-benzodioxane-2-acetonitrile (synthesizedinreference example 5), following compound having the following physicaldatawas given. ##STR335##

TLC: Rf 0.36 (methylene chloride: menthanol=5:1); NMR: δ7.88 (1H,d),7.70 (1H, d), 7.47 (2H, d), 7.20 (2H, d), 6.84 (1H, t), 6.63 (1H,dd), 6.57(1H, d), 3.36(2H, d); IR: ν3300, 3200-2300, 1660, 1605, 1530,1460 cm⁻¹ ; Mass: m/e 433(M⁺), 233, 201; Appearance: dark brown powder.

EXAMPLE 2(302)-2(303)

By the same procedure as example 2, using with a corresponding nitrile,following compounds having the following physical data were given.##STR336##

TLC: 0.3 (methylene chloride: methanol=5:1); IR: ν1655, 1615, 1600,1540, 1490 cm⁻¹ ; Mass: m/e 391(M⁺), 349, 309, 217, 201, 191;Appearance: pale yellow powder ##STR337##

TLC: 0.22 (chloroform: methanol=9:1); IR: ν3300-2300, 2920, 1655, 1620,1540, 1470, 1350, 1045, 980 cm⁻¹ ; Mass: m/e 407(M⁺), 324, 292, 201;Appearance: pale yellow crystal.

EXAMPLE 3

Synthesis of8-(p-pentylcinnamoyl)amino-4-oxo-4H-1-benzopyran-2-carboxylic acid ethylester ##STR338##

Oxalyl chloride (3.4 ml) was added to p-pentylcinnamic acid (327 mg),and the mixture was stirred for 30 min at room temperature. Excessoxyalyl chloride was removed from the mixture under reduced pressure.The residue was dissolved to methylene chloride (5 ml). In an atmosphereof argon, a solution of 8-amino-4-oxo-4H-1-benzopyran-2-carboxylic acidethyl ester (420 mg) in a mixture of methylene chloride (5 ml) andtriethylamine (0.6 ml) was added slowly. The reaction solution wasstirred for 1 hr at room temperature, and then poured into 0.1Nhydrochloric acid. The mixture was extracted with ethyl acetate. Theextract was washed with water, a saturated aqueous solution of sodiumbicarbonate and a saturated aqueous solution of sodium chloride,successively, dried, and concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel (ethylacetate: hexane=1:3) to give the title compound (140 mg)having thefollowing physical data:

TLC: Rf 0.60 (ethyl acetate: hexane=1:1); NMR (CDCl3): δ8.76(1H,dd),8.23(1H, s), 7.72(1H, dd), 7.65(1H, d), 7.38(2H, d), 7.27(1H, t),7.07 (2H,d), 7.00 (1H, s), 6.52 (1H, d); IR: ν3270, 2930, 1730, 1660,1630, 1530,1430, 1290, 1260, 1180, 770 cm⁻¹ ; Mass: m/e 433(M⁺), 404,388, 376, 360, 318, 233, 201, 131; Appearance: white powder.

EXAMPLE 4

Synthesis of8-(p-pentylcinnamoyl)amino-4-oxo-4H-1-benzopyran-2-carboxylic acid##STR339##

8-(p-pentylcinnamoyl)amino-4-oxo-4H-1-benzopyran-2-carboxylic acid ethylester (132 mg; synthesized in example 3) was dissolved into ethanol (10ml). To the solution, an aqueous solution (1 ml) of sodium bicarbonate(126 mg) was added. The mixture was refluxed for 15 min. To the reactionsolution mixture cooled to room temperature, water (20 ml) and 1Nhydrochloric acid (2 ml) were added. The mixture was extracted withethyl acetate. The extract was washed with water and a saturated aqueoussolution of sodium chloride, dried, and concentrated under reducedpressure. The residue was washed with a mixture of ethyl acetate andhexane (1:1), and dried to give the title compound (62 mg) having thefollowing physical data:

TLC: Rf 0.25 (ethyl acetate: methanol=5:1); NMR: δ8.66(1H, dd), 7.86(1H,dd), 7.73(1H, d), 7.53(2H, d), 7.43(1H, t), 7.22(2H, d), 7.15(1H,s),7.08(1H, d); IR: ν3400, 2930, 1635, 1520, 1430, 1360 cm⁻¹ ; Mass: m/e405(M⁺), 361, 201, 181, 169, 131, 69; Appearance: yellow powder.

EXAMPLE 4(1)-4(3)

By the same procedure as example 3 and 4, using with a correspondingcarboxylic acid and 8-amino-4-oxo-4H-1-benzopyran-2-carboxylic acidethyl ester which have corresponding substituent R³ following compoundshaving the following physical data, shown in table [XIV] were given.##STR340##

    TABLE XIV       Example Substituent R, R.sup.3 Rf value in TLC     No. in the general     formula (Iq) (developing solvent) NMR (δppm) IR (νcm.sup.-1)     Mass Appearance              4(1)      0.2(methylene chloride:methanol = 5:1) 8.90(1H, dd), 7.88(1H, dd),     7.74(1H,d), 7.5-7.6(2H, m), 7.46(1H, t), 7.18(1H,s), 6.95-7.05(2H, m),     6.88(1H,d), 4.70(2H, t) 1650, 1630, 1600,1580, 1540, 1510 459 (M.sup.+)41     5, 351255, 164147 pale yellow powder       4(2)     ##STR341##      0.20(ethyl acetate:methanol = 5:1) 8.75(1H, d), 7.76(1H, d), 7.68(1H,     m),7.54(2H, d), 7.22(2H, d), 7.16(1H, s),6.99(1H, d), 2.64(2H, t),     2.50(3H, s),1.64(2H, m), 1.20-1.50(4H, m),0.90(3H, t) 3450, 2930,     1850,1735, 1625, 1600,1535, 1445, 1270,1210, 1180,  980, 820 419 (M     .sup.+)219, 201,131 pale yellow powder       4(3)     ##STR342##      0.17(chloroform:methanol = 4:1) 8.46(1H, dd), 7.92(1H, dd), 7.92(2H,d),     7.46(1H, t), 7.32(2H, d), 7.08(1H,s), 2.70(2H, t), 0.90(3H, t) 3270,     1700, 1650,1630, 1620, 1580,1525, 1440, 1360 175, 173 yellow powder

EXAMPLE 4(101)-4(104)

By the same procedure as example 3 and 4, using with correspondingcarboxylic acid and 8-amino-1,4-benzodioxane-2-carboxylic acid ethylester, following compounds having the following physical data, shown intable [XV were given. ##STR343##

    TABLE XV       Example Substituent R Rf value in TLC     No. in the general formula     (Ir) (developing solvent) NMR (δppm) IR (νcm.sup.-1) Mass     Appearance              4(101)      0.10(ethyl acetate:methanol = 10:1) (CD.sub.3 OD) 7.80(1H, d), 7.62(1H,     d), 7.50(2H, d), 7.20(2H, d), 6.92(1H, d), 6.78(1H,t), 6.62(1H, dd),     4.70(1H, dd), 4.54(1H,dd), 4.18(1H, dd), 2.62(2H, t), 1.62(2H, m),1.20-1.     45(4H, m), 0.90(3H, t) 3300, 2930, 2850,1610, 1530, 1440,1260, 1180,     1100, 975,  825,  770 395 (M.sup.+)351, 201195, 161127,  85 white powder       4(102)     ##STR344##      0.37(chloroform:methanol = 4:1) 7.92(2H, d), 7.69(1H, dd), 6.95(2H,     6     dd),.84(1H, t), 6.66(1H, dd), 4.66(1H, m), 4.45(1H, dd), 4.27(1H, dd),     4.02(2H, t),1.81(2H, m), 1.31(8H, m), 0.88(3H, t) 3650-2400, 1605,1440,     1250, 1170,1080,  895,  840, 770 409 (M.sup.+)233 pale yellow crystal     4(103)      ##STR345##      0.39(chloroform:methanol = 4:1) 7.91(2H, d), 7.71(1H, dd), 6.96(2H,     d),6.93(1H, t), 6.65(1H, dd), 5.78(2H, m),4.68(1H, m), 4.53(2H, d),     4.41(1H, m),4.31(1H, m), 2.09(2H, m), 1.32(6H, m),0.88(3H, t) 3650-2500,     1600,1450, 1255, 1180,1090, 1000,  840, 775 407,231 white powder     4(104)      ##STR346##      0.50(chloroform:methanol = 4:1) 7.92(2H, d), 7.72(1H, dd), 7.02(2H,     d),6.84(1H, t), 6.65(1H, dd), 4.72(3H, t),4.38(2H, m), 2.21(2H, m),     1.49(2H, m),1.32(4H, m), 0.87(3H, m) 3650-2500, 1605,1440, 1255,     1170,1080,  990,  890,  830,      760 405219 yellow brown powder

EXAMPLE 4(201)-4(208)

By the same procedure as example 4, using with a correspondingcarboxylic acid and a corresponding amine, following compounds havingthe following physical data, shown in table [XVI] were given.

    TABLE XVI       Example  Rf value in TLC     No. Formula (developing solvent) NMR     (δppm) IR (νcm.sup.-1) Mass Appearance              4(201)      ##STR347##      0.05(chloroform:meth-anol = 4:1) (CDCl.sub.3 + DMSO-d.sub.6)10.75(1H,     s), 8.62(1H, d), 7.90-8.10(3H, m), 7.40-7.65(2H, m), 7.10-7.35(5H, m),     7.00(2H, d), 4.07(2H, t),2.70(2H, t), 1.85(4H, m) 3250, 2930, 1630,      1     1600,490, 1250, 1175,  840, 755,  695 456 (m.sup.+),412, 394,262,     253,121,  91 white powder       4(202)     ##STR348##      0.05(chloroform:meth-anol = 4:1) (CDCl.sub.3 + DMSO-d.sub.6)10.72(1H,     s), 8.60(1H, d), 7.90-8.10(3H, m), 7.40-7.65(2H, m), 7.13(1H, dd),7.00(2H     , d), 6.91(1H, dd), 6.81(1H, d),4.07(2H, m), 2.92(2H, m), 1.90(4H, m)     3250, 2930, 1630, 1600,1500, 1250, 1250, 1175, 840,  760,  695 462     (m.sup.+),418, 400,276, 259,139, 121, 97 yellow brown powder   4(203)      ##STR349##      0.05 (chloroform:meth-anol = 4:1) 8.80(1H, dd), 7.98(2H, d), 7.92(1H,     dd),7.58(1H, s), 7.50(1H, d), 7.00(2H, d),5.60-6.00(3H, m), 4.85-5.10(2H,      m),4.55(2H, d), 2.10(4H, m), 1.50(2H, m) 3350, 3060, 2930, 1640,1605,     1500-1530, 1360,1255, 1175,  995,  965, 905,  840,  760  pale yellow     powder       4(204)     ##STR350##      0.47(methylenechloride:meth-anol = 5:1) 8.03(1H, dd), 7.93(2H, d),     7.36-7.14(5H, m), 7.04(1H, t), 6.96(2H, d),6.83(1H, dd), 5.45(1H, dd),     4.60(1H,dt), 4.15(1H, dt) 3400-2300, 1645, 1610,1510, 1480, 1450,     1260,1060 485 (m.sup.+),442, 439411, 377,359 white powder   4(205)      ##STR351##      0.33(cyclohexane:ethylacetate = 1:2) (CDCl.sub.3)9.1(1H, s), 8.53(1H,     d), 7.54(1H,d), 7.54(1H, s), 7.38(1H, t), 7.34(2H, d), 7.22(2H, d),     7.06(1H, t), 2,83(2H, t), 2.64(2H, t),2.48(2H, t), 2.28(3H, d), 1.89(2H,     m),1.65(2H, m), 1.33(4H, m), 0.90(3H, t) 3450, 3340, 2920, 2850,1710,     1660, 1610, 1500,1470, 1430, 1190 425 (m.sup.+),306, 215,145 white     powder       4(206)     ##STR352##      0.30(cyclohexane:ethyl acetate = 1:2) (CDCl.sub.3)8.54(1H, s), 8.50(1H,     d), 7.50(1H, d),7.42(2H, d), 7.35(1H, t), 7.20(2H, d),7.04(1H, t),     6.20(1H, d), 2.80(2H, t),2.60(5H, m), 2.48(2H, t), 1.88(2H, m),1.64(2H,     m), 1.35(4H, m), 0.90(3H, t) 3300, 2950, 2860, 1710,1640, 1480 425     (m.sup.+),306, 215,211 white powder 4(207)      ##STR353##      0.30(ethyl acetate:ethanol = 1:1) (CDCl.sub.3)8.64(1H, s), 8.52(1H, d),     7.75(1H, d),7.40-7.60(3H, m), 7.36(1H, t), 7.10-7.30(2H, m), 7.06(1H,     dt), 6.56(1H, d), 2.82(2H, t), 2.63(2H, t), 2.48(2H, t), 1.80-2.00(2H,     m) 1700, 1655, 1615, 1570,1520 411 (m.sup.+),292, 211,201 white powder     4(208)      ##STR354##      0.05(chloroform:methanol = 4:1) (CDCl.sub.3 + DMSO-d.sub.6):10.70(1H,     s), 8.50(1H, dd),8.00(3H, m), 7.50(2H, m),7.02(2H, d), 5.60-6.00(3H,     m),4.85-5.10(2H, m), 4.58(2H, d),2.10(4H, m), 1.50(2H, m) 3280, 2950,     1640,1605, 1590, 1500,1260, 1180, 1100,      760  pale yellow powder

EXAMPLE 4(301)-4(320)

By the same procedure as example 4, using with a correspondingcarboxylic acid and a corresponding amine, following compounds havingthe following physical data, shown in table [XVII] were given.

                                      TABLE XVII                                  __________________________________________________________________________    Example                                   Rf value in TLC Appear-             No.  Formula                              (developing solvent)                                                                     Mass ance                __________________________________________________________________________    4(301)                                                                              ##STR355##                          0.48 (ethyl acetate)                                                                     383 (M.sup.+), 365,                                                           292, 201                                                                           pale yellow                                                                   crystal             4(302)                                                                              ##STR356##                          0.4 (ethyl acetate: hexane =                                                  1:1)       397 (M.sup.+), 292,                                                           201, 197,                                                                          white powder        4(303)                                                                              ##STR357##                          0.10 (methylene                                                                          395 (M.sup.+), 287,                                                           258, 229,                                                                          pale brown                                                                    powder              4(304)                                                                              ##STR358##                          0.2 (cyclohexane: ethyl acetate                                               = 1:2)     383 (M.sup.+), 264,                                                           211, 173                                                                           white powder        4(305)                                                                              ##STR359##                          0.3 (cyclohexane: ethyl acetate                                               = 1:2)     423 (M.sup.+), 304,                                                           213, 211, 187,                                                                     white powder        4(306)                                                                              ##STR360##                          0.24 (cyclohexane:  ethyl                                                     acetate = 1:2)                                                                           431 (M.sup.+), 312,                                                           221, 211, 125,                                                                     white powder        4(307)                                                                              ##STR361##                          0.26 (cyclohexane: ethyl                                                      acetate = 1:2)                                                                           465 (M.sup.+), 346,                                                           255, 245, 211,                                                                     pale yellow                                                                   powder              4(308)                                                                              ##STR362##                          0.43 (ethyl acetate)                                                                     429 (M.sup.+), 231,                                                           229, 201                                                                           white crystal       4(309)                                                                              ##STR363##                          0.34 (ethyl acetate)                                                                     515 (M.sup.+), 412,                                                           307  white crystal       4(310)                                                                              ##STR364##                          0.39 (ethyl acetate: hexane =                                                 1:1)       439 (M.sup.+),                                                                     white crystal       4(311)                                                                              ##STR365##                          0.34 (ethyl acetate)                                                                     459 (M.sup.+), 461,                                                           424, 349,                                                                          white crystal       4(312)                                                                              ##STR366##                          0.44 (ethyl acetate)                                                                     465 (M.sup.+),                                                                     white crystal       4(313)                                                                              ##STR367##                          0.34 (ethyl acetate)                                                                     419 (M.sup.+),                                                                     pale brown                                                                    crystal             4(314)                                                                              ##STR368##                          0.23 (ethyl acetate: hexane =                                                 1:1)       515 (M.sup.+), 355,                                                           321, 161                                                                           white powder        4(315)                                                                              ##STR369##                          0.38 (ethyl acetate: hexane =                                                 1:1)       415 (M.sup.+),                                                                     white crystal       4(316)                                                                              ##STR370##                          0.06 (ethyl acetate: hexane =                                                 1:3)       549 (M.sup.+), 515,                                                           463, 355, 195,                                                                     white crystal       4(317)                                                                              ##STR371##                          0.22 (ethyl acetate: hexane =                                                 1:1)       499 (M.sup.+), 394,                                                           305  white crystal       4(318)                                                                              ##STR372##                          0.22 (ethyl acetate: hexane =                                                 1:1)       435 (M.sup.+),                                                                     pale yellow                                                                   powder              4(319)                                                                              ##STR373##                          0.18 (ethyl acetate: hexane =                                                 1:1)       503 (M.sup.+), 417,                                                           400, 399, 398,                                                                     white powder        4(320)                                                                              ##STR374##                          0.21 (ethyl acetate: hexane =                                                 1:1)       515 (M.sup.+), 429,                                                           355, 321                                                                           white crystal       __________________________________________________________________________

EXAMPLE 5

Synthesis of8-[p-(4-phenylbutoxy)benzoylamino]-2-(5-tetrazolyl)-2,3-dihydrobenzoxazine##STR375##

In an atmosphere of argon, a mixture8-[p-(4-phenylbutoxy)benzoylamino]-N-trifluoroacetyl-2,3-dihydrobenzoxazin-2-nitrile(316 mg), sodium azide (196 mg) ammonium chloride (161 mg) anddimethylformamide (2.5 ml was stirred for 1 hr at 100° C. Afterreaction, the reaction solution was poured into a mixture of ice anddil. hydrochloric acid, and the mixture was extracted with ethylacetate. The extract was washed, dried over magnesium sulphate, andcondensed under reduced pressure. The residue was dissolved into ethanolwhich was saturated with ammonia (50 ml). The solution was stirred for20 hrs at room temperature and then concentrated under reduced pressure.The residuewas purified by column chromatography on silica gel(chloroform:methanol=3:1) to give the title compound (207 mg) having thefollowing physical data:

TLC: Rf 0.36 (chloroform: methanol=3:1) IR: ν3600-2300, 1630, 1600,1500, 1465, 1250, 1170 cm⁻¹ ; Mass: m/e 470 (M⁺), 376, 358,253;Appearance: brown powder.

EXAMPLE 5(1)-5(10)

By the same procedure as example 5, using with a corresponding nitrile,following compounds having the following physical data, shown in table[XVII] were given.

    TABLE XVIII       Example  Rf value in TLC     No. Formula (developing solvent) NMR     (δppm) IR (νcm.sup.-1) Mass Appearance              5(1)      ##STR376##      0.30(methylene chloride:methanol = 5:1) 809(1H, dd), 7.88(2H, d),     7.40-7.00(8H, m), 6.95(2H, d), 5.54(2H, s),4.03(2H, t), 2.71(2H, t),     1.95-1.75(4H, m) 3350, 3100-2300, 1610,1600, 1560, 1530, 1510,1450, 1260 4     43 (m.sup.+),361, 343,253 white powder       5(2)     ##STR377##      0.30(methylene chloride:methanol = 5:1) (CDCl.sub.3)8.10(1H, s),     7.68(2H, d), 7.76-7.64, 64(1H,d), 7.05(1H, t), 6.92(1H, t), 6.82(2H,d),     6.72(1H, d), 6.00-5.58(2H, m),5.46(2H, d), 4.47(2H, d) 3200, 3100-2300,     1600,1590, 1560, 1525, 1500,1250 421 (m.sup.+),331, 311, 301, 231 white     powder       5(3)     ##STR378##      0.36(methylene chloride:methanol = 3:1) 7.88(2H, d), 7.22(6H, m),     6.93(2H, d),6.79(1H, t), 6.47(1H, dd), 5.68(1H, t),4.02(2H, t), 3.89(1H,     dd), 3.73(1H, dd),2.67(2H, m), 1.84(4H, m) 3600-2300, 1630, 1600,1500,     1465, 1250, 1170 470 (m.sup.+),376, 358,253 brown powder       5(4)     ##STR379##      0.20(chloroform:methanol = 4:1) (CDCl.sub.3 + CD.sub.3 OD +      DMSO-d.sub.6)8.06(2H, d), 7.85(1H, d), 7.74(1H, d),7.64(1H, d),     7.46(1H, m), 7.38(1H, d),7.27(1H, dd), 7.03(2H, d), 5.80(1H, m),5.53(2H,     s), 5.00(2H, m), 4.06(2H, t),2.08(2H, m), 1.83(2H, m), 1.45(6H, m) 3220,     2930, 2850, 1620,1600, 1495, 1250, 1225,1170, 1055,  840,  825 471     (m.sup.+),389, 231,121 grey powder       5(5)     ##STR380##      0.20(chloroform:methanol = 4:1) (DMSO-d.sub.6)8.06(2H, d), 7.95(1H, d),     7.80(1H, d),7.61(1H, d), 7.20-7.55(8H, m), 7.10(2H, d), 5.58(2H, s),     4.31(2H, t), 3.30(1H, s), 3.10(2H, t) 3270, 1620, 1600, 1490,1260, 1175,      835 465 (m.sup.+),422, 383,262, 225,121, 105 grey powder   5(6)      ##STR381##      0.20(chloroform:methanol = 4:1) (DMSO-d.sub.6)8.04(2H, d), 7.94(1H, d),     7.78(1H, d),7.60(1H, d), 7.49(1H, d), 7.41(1H, t),7.35-7.11(6H, m),     7.06(2H, d), 5.58(2H, s), 4.09(2H, t) 3500-2300, 1620, 1600,1570, 1520,     1490, 1250 493 (m.sup.+),411, 253 grey powder       5(7)     ##STR382##      0.34(chloroform:methanol = 4:1) 7.77(1H, d), 7.56-6.89(7H, m),6.47(2H,     d), 6.20(1H, dd), 3.87(1H,dd), 2.62(2H, t), 0.90(3H, t) 3300, 2950,     1670, 1630,1540, 1450, 1190 403 (m.sup.+),346, 328,201 pale brown powder       5(8)     ##STR383##      0.10(chloroform:methanol = 4:1)   428 (M.sup.+),410, 400,296, 201     yellow powder       5(9)     ##STR384##      0.24(chloroform:methanol = 3:1)   418 (M.sup.+),201 white powder     5(10)      ##STR385##      0.7(methylenechloride:methanol =      3:1)   296, 253 yellow powder

EXAMPLE 6

Synthesis of 4-[2-(p-pentyl-2-methylcinnamoyl)-aminophenoxy]-butanoicacid and ethyl ester thereof. ##STR386##

A mixture of 2-(p-pentyl-2-methylcinnamoyl)aminophenol (267 mg),4-bromobutanoic acid ethyl ester (322 mg), potassium carbonate (135 mg)and acetone (2 ml) was refluxed overnight. After cooling, the reactionsolution was diluted with ethyl acetate, precipitation was removed byfiltration from the solution. The solution was concentrated underreduced pressure to give the title compound (ester) having the followingphysical data:

TLC: Rf 0.66 (toluene: ethyl acetate=10:1); Mass: m/e 437(M⁺).

Ester obtained was dissolved into methanol (3.2 ml). To the solution, a2N aqueous solution of sodium hydroxide (1.64 ml), and the solution wasstirred for 1.5 hrs at 40° C. After reaction, the solution was acidifiedwith dil. hydrochloric acid. The mixture was extracted with ethylacetate. The extract was washed with water, dried and concentrated underreduced pressure to give the title compound (acid; 285 mg) having thefollowing physical data:

TLC: Rf 0.60 (methylene chloride: methanol=5:1); IR ν3470, 3200-2300,1710, 1670, 1620, 1600, 1530, 1450, 750 cm⁻¹ ; NMR (CDCl₃): δ8.44 (1H,dd), 8.28 (1H, s), 7.45 (1H, s), 7.30 (2H, d), 7.18(1H, dd), 4.11(2H,t); Mass: m/e 409(M⁺), 215, 187; Appearance: white powder.

EXAMPLE 6(1)-6(2)

By the same procedure as Example 6, using a corresponding phenol,followingcompounds were given. ##STR387##

TLC: Rf 0.48 (ethyl acetate); IR: ν3320, 3200-2300, 1700, 1660, 1630,1610, 1540 cm⁻¹ ; NMR (CDCl3): δ8.40(1H, d), 8.22(1H, s), 7.60(1H, d),7.34(2H, s), 7.04(2H, d), 6.85(1H, dd), 6.76(1H, d), 6.69(1H,dd); Mass:m/e 395 (M⁺), 201, 195; Appearance: white powder. ##STR388##

TLC: 0.4 (methylene chloride: methanol=5: 1 ); IR: ν1655, 1600, 1520,1445 cm⁻¹ ; Mass m/e 445(M⁺), 363, 345, 255, 191, 147; Appearance: paleyellow powder.

EXAMPLE 7

Synthesis of8-[3-(p-pentylphenyl)propionyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane##STR389##

8-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane (216 mg;synthesized in example 2(1)) and palladium-carbon (50 mg; content 5%)weresuspended in a mixed solvent (6 ml) of methanol, ethanol and ethylacetate (1:1:1). In an atmosphere of hydrogen, the suspension wasstirred for 90 min at room temperature. After stirring, the suspensionwas filtered through celite. The filtrate was condenced under reducedpressure. Thre residue was purified by column chromatography on silicagel (methylene chloride: methanol=19:1) to give the title compound (202mg) having the following physical data:

TLC: Rf 0.54 (methylene chloride: methanol=4:1); NMR (CDCl₃): δ7.28(1H,s), 7.11(4H, 2d), 6.76(2H, m), 6.60(1H, dd), 5.68(1H, t), 4.93(1H, dd),3.04(2H, t), 2.77(2H, m), 2.56(2H, t), 1.58 (2H, m), 1.30 (4H, m), 0.88(3H, t); IR: ν3600-2300, 1650, 1615, 1530, 1460, 1260, 1100, 780 cm⁻¹ ;Mass: m/e 421(M⁺), 219; Appearance: white crystal.

EXAMPLE 8

Synthesis of8-[p-(6-hydroxyhexyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane##STR390##

A 1N aqueous solution of sodium hydroxide (0.5 ml) was added to asolution of8-[p-(6-acetyloxyhexyloxy)benzoyl]-amino-2-(5-tetrazolyl)-1,4-benzodioxane(100mg; synthesized in example 1 (96)) in methanol (0.5 ml) at roomtemperature. The reaction solution was stirred for 10 min at the sametemperature, and then concentrated under reduced pressure. To theresidue,dil. hydrochloric acid was added and the mixture was extractedwith ethyl acetate. The extract was dried and concentrated under reducedpressure. The residue was purified by column chromatography on silicagel (methylenechloride: methanol=100:1) to give the title compound (95mg) having the following physical data:

TLC: Rf 0.23 (methylene chloride: methanol=5:1); NMR: δ7.89 (2H, d),7.46 (1H, dd), 6.95 (2H, d), 6.92(1H, t), 6.76(1H, dd), 4.02(2H, t),3.60 (2H, t); IR: ν3400, 3200-2300, 1630, 1600, 1520, 1500, 1440, 1250cm⁻¹ ; Mass m/e 439(M⁺), 221, 149, 121; Appearance: white amorphous.

EXAMPLE 9

Synthesis of 8-[p-[5-(N ,N-dimethylamino)pentyloxy]cinnamoyl]-amino-1,4-benzodioxane sodium salt ##STR391##

A 40% aqueous solution of dimethylamine (1 ml) was dropped to a solutionof8-[p-(5-bromopentyloxy)cinnamoyl]-amino-1,4-benzodioxane (176 mg;synthesized in example 1(113)). The solution was stirred for 1 hr atroom temperature. Volatile matter was removed with vacuum pump for 1 hrat roomtemperature, and for 3 hrs at 90° C. The residue was dissolvedinto methanol (1 ml), to the solution, a 2N aqueous solution of sodiumhydroxide (360 μl). The mixture was condensed under reduced pressure. Tothe residue, small amount of methanol and hexane (4 ml) were added.Themixture was filtered, and volatile matter was removed from thefiltrate with vacuum pump overnight at room temperature and overnight at80°C. to give the title compound (179 mg) having the following physicaldata:

TLC: Rf 0.33 (ethyl acetate: acetic acid: water=3:1:1); NMR: δ7.87(2H,d), 7.62(1H, dd), 6.98(2H, d), 6.86 (1H, t), 6.71 (1H, dd), 4.06 (2H,t), 2.85(2H, t), 2.64(2H, s); IR: ν3430, 2930, 1655, 1605, 1505, 1445,1255 cm⁻¹ ; Mass: m/e 452 (M⁺), 233; Appearance: white powder.

EXAMPLE 10

Synthesis of8-(p-octyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane-7-carboxylicacid ##STR392##

8-(p-octyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane-7-carboxylicacid methyl ester (332 mg; synthesized in example 2(107) was dissolvedin methanol (1.5 ml). To the solution, a 1N aqueous solution of sodiumhydroxide (1.36 ml), and the mixture was stirred for 50 min at roomtemperature and for 2 hrs at 40° C. After cooling, 1N hydrochloric acid(2 ml) was added to the solution. The mixture was extracted with ethylacetate. The extract was dried and concentrated under reduced pressure.The residue was purified by column chromatography on silica gel(chloroform: methanol=9:1) to give the title compound (263 mg) havingthe following physical data:

TLC: Rf 0.15 (chloroform: methanol=4:1); NMR: δ8.00 (2H, d), 7.68 (1H,d), 6.98 (2H, d), 6.82 (1H, d), 6.04 (1H, m), 4.56 (2H, m), 4.03 (2H,t),1.82 (2H, m), 1.31 (10H, m), 0.88 (3H, t); IR: 3600-2300, 1680, 1640,1600, 1490, 1460, 1250, 1170, 1080, 900, 840, 760 cm⁻¹ ; Mass: m/e 495(M⁺), 477, 383, 233; Appearance: pale brown powder.

EXAMPLE 11

Synthesis of8-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-6-methyl-1,4-benzodioxanesodium salt ##STR393##

8-(p-pentylcinnamoyl)-2-(5-tetrazolyl)-6-methyl-1,4-benzodioxane (50 mg;synthesized in example 2(103)) was dissolved in methanol (0.5 ml). Tothe solution, equivalent molar of a 1N aqueous solution of sodiumhydroxide was added. The solution was stirred and then evaporated todryness to givethe title compound (51 mg).

EXAMPLE 11(1)

By the same procedure as example 11, corresponding sodium salts of thecompounds synthesized in examples (other than example 11 and esters)were given.

EXAMPLE 12

8-[p-(3E-hexenyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane (0.5g), cellulose calcium gluconate (200 mg; disintegrator), magnesiumstearate (100 mg; lubricator) and microcrystalline cellulose (9.2 g)were admixed and punched out in conventional manner to give 100 tabletseach containing 5 mg of the active ingredient.

What is claimed is:
 1. A novel (fused) benz(thio)amide of the generalformula: ##STR394## or a non-toxic salt thereof, wherein A represents asingle bond;B represents a divalent group of the formula ##STR395## Trepresents an oxygen atom or a sulphur atom; R¹ represents a group ofthe general formula: ##STR396## wherein R⁵ and R⁶ independentlyrepresent a hydrogen atom; a halogen atom; or a straight or branchedalkyl, alkenyl or alkynyl group having from 1 to 20 carbon atoms beingunreplaced or having one, two, three, four or five optional carbonatom(s) replaced by oxygen atom(s), sulphur atom(s), halogen atom(s),nitrogen atom(s), benzene ring(s), thiophene ring(s), naphthalenering(s), carbocyclic ring(s) of from 4 to 7 carbon atom(s), carbonylgroup(s), carbonyloxy group(s), hydroxy group(s), carboxy group(s),azido group(s) or nitro group(s); R² represents a hydrogen atom; R³represents a hydrogen atom; R⁴ represents a group of the generalformula: ##STR397## wherein R⁸ represents a hydrogen atom or a straightor branched alkyl group of from 1 to 6 carbon atom(s);p represents aninteger from 1 to 10; and q represents zero or an integer of from 1 to10;with the following provisos (A) and (B): (A) compounds of the generalformula (I') and non-toxic salts therefore are excluded: ##STR398##wherein: A' represents a single bond,R^(4') represents

    --(CH.sub.2).sub.s --COOR.sup.8

wherein s is an integer of 1 or 2 and R⁸ has the same meaning as definedabove, and R^(1') represents ##STR399## wherein R^(5') and R.sup. 6'each independently represents a hydrogen atom; a hydroxy group; ahalogen atom; a straight or branched alkyl, alkenyl, alkynyl, alkoxy,alkenyloxy, alkynyloxy or acyloxy group having from 1 to 4 carbon atoms;a cycloalkyl group having from 3 to 6 carbon atoms; or a straight orbranched alkyl group having from 1 to 20 carbon atoms substituted by atleast one halogen atom; and (B) compounds of the general formula (I")and non-toxic salts thereof are excluded: ##STR400## wherein: A"represents a single bond,R^(4') represents ##STR401## wherein q is 0,and R^(1") represents ##STR402## wherein either (i) R^(5") represents ahydrogen atom and R^(6") represents a straight or branched alkyl grouphaving from 1 to 4 carbon atoms, a halogen atom or a trifluoromethylgroup; or (ii) R^(5") and R^(6") each represents a halogen atom.
 2. Acompound according to claim 1, wherein B represents said divalent groupof the formula ##STR403##
 3. A compound according to claim 2, wherein Trepresents an oxygen atom.
 4. A compound according to claim 3, whereinR¹ represents a group of the general formula: ##STR404## wherein R⁵ andR⁶ each has the same meaning as defined in claim
 1. 5. A compoundaccording to claim 4, which is selected from the group consistingof:N-[p-(4-phenylbutoxy)benzoyl]-2-(5-tetrazolyl)methoxyanilide,N-[p-(2E-octenyloxy)benzoyl]-2-(5-tetrazolyl)methoxyanilide,N-[2-[p-(3-phenylthiopropoxy)benzoyl]aminophenoxy]butanoic acid,4-[2-[P-(5-chloropentyloxy)benzoyl]aminophenoxy]butanoic acid,4-[2-(m-pentyloxy-o-methoxybenzoyl)aminophenoxy]butanoic acid,and sodiumsalts thereof.
 6. A compound according to claim 1, wherein B representssaid divalent group of the formula ##STR405##
 7. A compound according toclaim 6, wherein T represents an oxygen atom.
 8. A compound according toclaim 7, wherein R¹ represents a group of the general formula:##STR406## wherein R⁵ and R⁶ each has the same meaning as defined inclaim
 1. 9. A pharmaceutical composition comprising, as activeingredient, at least one pharmaceutically active compound of generalformula (I) as defined in claim 1 or a non-toxic salt thereof, togetherwith at least one of a pharmaceutical carrier and a coating.
 10. Amethod for the prevention of diseases which are induced by leukotrienesor for the treatment of diseases which are induced by leukotrienes,comprising administering a therapeutically effective amount of acompound of general formula (I) as defined in claim 1, or a non-toxicsalt thereof.
 11. A method for the prevention of diseases which areinduced by 5α-reductase, or for the treatment of diseases which areinduced by 5α-reductase, comprising administering a therapeuticallyeffective amount of a compound of general formula (I) as defined inclaim 1, or a non-toxic salt thereof.
 12. A novel (fused)benz(thio)amide of the general formula: ##STR407## or a non-toxic saltthereof, wherein A represents a single bond;B represents a divalentgroup of the formula: ##STR408## T represents an oxygen atom or asulphur atom; R¹ represents a group of the general formula (i):##STR409## wherein R⁵ represents a hydrogen atom, or an alkoxy oralkenyloxy group having 4 to 8 carbon atoms; and R⁶ represents an alkoxyor alkenyloxy group having 4 to 8 carbon atoms, a phenylalkoxy groupwherein the alkyl moiety has 4 to 8 carbon atoms, or a phenylalkenyloxygroup wherein the alkyl moiety has 4 to 8 carbon atoms; R² represents ahydrogen atom; R³ represents a hydrogen atom; R⁴ represents generalformula: ##STR410## wherein R⁸ represents a hydrogen atom or a straightor branched alkyl group of from 1 to 6 carbon atom(s);p represents aninteger from 1 to 10; and q represents zero or an integer of from 1 to10;with the following provisos (A) and (B): (A) compounds of the generalformula (I') and non-toxic salts thereof are excluded: ##STR411##wherein A' represents a single bond,R^(1') represents ##STR412## whereinR^(5') represents a hydrogen atom, or an alkoxy or alkenyloxy grouphaving 4 carbon atoms; and R.sup. 6' represents an alkoxy or alkenyloxygroup having 4 carbon atoms, a phenylalkoxy group wherein the alkylmoiety has 4 carbon atoms, or a phenylalkenyloxy group wherein the alkylmoiety has 4 carbon atoms; and R^(4') represents

    --(CH.sub.2).sub.s --COOR.sup.8

wherein s is an integer of 1 or 2 and R⁸ has the same meaning as definedabove; and (B) compounds of the general formula (I') and non-toxic saltsthereof are excluded: ##STR413## wherein A' represents a singlebond;R^(1") has the same definition as R^(1') above; and R^(4")represents ##STR414## wherein q is
 0. 13. A novel (fused)benz(thio)amide as claimed in claim 12, whereinB represents a divalentgroup of the formula: ##STR415## and R¹ and R^(1') each represents agroup of the general formula (i): ##STR416## wherein R⁵ represents ahydrogen atom and R⁶ represents an alkoxy or phenylalkoxy group.
 14. Anovel (fused) benz(thio)amide as claimed in claim 13, represented by theformula: ##STR417## wherein: R⁴ has the same definition as R⁴ in claim12; andR⁹ represents an alkyl group having 4 to 8 carbon atoms, or aphenylalkyl group in which the alkyl moiety has 4 to 8 carbon atoms. 15.A novel (fused) benz(thio)amide as claimed in claim 14, wherein R⁹represents an alkyl group.
 16. A novel (fused) benz(thio)amide asclaimed in claim 14, wherein R⁹ represents a phenylalkyl group.
 17. Anovel (fused) benz(thio)amide as claimed in claim 16, wherein R⁹represents a straight chain 4-phenyl-n-butyl group.
 18. A novel (fused)benz(thio)amide represented by the formula: ##STR418##
 19. A method forthe prevention of diseases which are induced by leukotrienes or for thetreatment of diseases which are induced by leukotrienes, comprisingadministering a therapeutically effective amount of a compound ofgeneral formula (I) as defined in claim 12, or a non-toxic salt thereof.20. The method according to claim 19, wherein in said compound ofgeneral formula (I):B represents a divalent group of the formula:##STR419## and R¹ and R^(1') each represents a group of the generalformula (i): ##STR420## wherein R⁵ represents a hydrogen atom and R⁶represents an alkoxy or phenylalkoxy group.
 21. The method according toclaim 20, wherein said compound is represented by the formula:##STR421## wherein: R⁴ has the same definition as R⁴ in claim 12; andR⁹represents an alkyl group having 4 to 8 carbon atoms, or a phenylalkylgroup in which the alkyl moiety has 4 to 8 carbon atoms.
 22. The methodaccording to claim 21, wherein in said compound R⁹ represents an alkylgroup.
 23. The method according to claim 21, wherein in said compound R⁹represents a phenylalkyl group.
 24. The method according to claim 23,wherein in said compound R⁹ represents a straight chain 4-phenyl-n-butylgroup.
 25. The method according to claim 24, wherein said compound isrepresented by the formula: ##STR422##
 26. A method for the preventionof diseases which are induced by 5α-reductase, or for the treatment ofdiseases which are induced by 5α-reductase, comprising administering atherapeutically effective amount of a compound of general formula (I) asdefined in claim 12, or a non-toxic salt thereof.
 27. The methodaccording to claim 26, wherein in said compound:B represents a divalentgroup of the formula: ##STR423## and R¹ and R^(1') each represents agroup of the general formula (i): ##STR424## wherein R⁵ represents ahydrogen atom and R⁶ represents an alkoxy or phenylalkoxy group.
 28. Themethod according to claim 27, wherein said compound is represented bythe formula: ##STR425## wherein: R⁴ has the same definition as R⁴ inclaim 12; andR⁹ represents an alkyl group having 4 to 8 carbon atoms, ora phenylalkyl group in which the alkyl moiety has 4 to 8 carbon atoms.29. The method according to claim 28, wherein in said compound R⁹represents an alkyl group.
 30. The method according to claim 28, whereinin said compound R⁹ represents a phenylalkyl group.
 31. The methodaccording to claim 30, wherein in said compound R⁹ represents a straightchain 4-phenyl-n-butyl group.
 32. The method according to claim 31,wherein said compound is represented by the formula: ##STR426##
 33. Apharmaceutical composition comprising, as active ingredient, at leastone pharmaceutically active compound of general formula (I) as definedin claim 12 or a non-toxic salt thereof, together with at least one of apharmaceutical carrier and a coating.
 34. A novel (fused)benz(thio)amide represented by the formula: ##STR427##
 35. A method forthe prevention of diseases which are induced by leukotrienes or for thetreatment of diseases which are induced by leukotrienes, comprisingadministering a therapeutically effective amount of the compound asdefined in claim 34, or a non-toxic salt thereof.
 36. A method for theprevention of diseases which are induced by 5α-reductase, or for thetreatment of diseases which are induced by 5α-reductase, comprisingadministering a therapeutically effective amount of the compound asdefined in claim 34, or a non-toxic salt thereof.
 37. A pharmaceuticalcomposition comprising, as active ingredient, at least onepharmaceutically active compound as defined in claim 34 or a non-toxicsalt thereof, together with at least one of a pharmaceutical carrier anda coating.